Submissions for variant NM_002273.4(KRT8):c.184G>T (p.Gly62Cys)

gnomAD frequency: 0.00545  dbSNP: rs11554495

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Mendelics	RCV002247346	SCV002518578	benign	not specified	2022-05-04	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000056938	SCV004133387	likely benign	not provided	2023-07-01	criteria provided, single submitter	clinical testing	KRT8: BS2
Labcorp Genetics (formerly Invitae), Labcorp	RCV000056938	SCV004467466	benign	not provided	2023-12-23	criteria provided, single submitter	clinical testing
Breakthrough Genomics, Breakthrough Genomics	RCV000056938	SCV005232364	benign	not provided		criteria provided, single submitter	not provided
OMIM	RCV000015735	SCV000036000	uncertain significance	Cirrhosis, cryptogenic	2003-05-13	no assertion criteria provided	literature only
Epithelial Biology; Institute of Medical Biology, Singapore	RCV000056938	SCV000088051	not provided	not provided		no assertion provided	not provided
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000056938	SCV001553834	likely benign	not provided		no assertion criteria provided	clinical testing	The KRT8 p.Gly62Cys variant was identified in 33 of 4270 proband chromosomes (frequency: 0.0077) from individuals with liver disease but was also present in 13 of 2056 control chromosomes (frequency: 0.0063) from healthy individuals, suggesting no association with liver disease (Halangk_2004_PMID:15235035; Ku_2003_PMID:12724528). Analysis of the p.G62C variant in a cohort of 217 German patients with Crohn' s disease, 131 German patients with ulcerative colitis, and 560 German control subjects also did not identify an association of this variant with Crohn's or ulcerative colitis (Büning_2004_PMID:15248378). The variant was identified in dbSNP (ID: rs11554495), ClinVar (classification not provided by Epithelial Biology; Institute of Medical Biology, Singapore) and LOVD 3.0 (classified as likely benign). The variant was identified in control databases in 1370 of 280620 chromosomes (7 homozygous) at a frequency of 0.004882 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: European (non-Finnish) in 1176 of 127714 chromosomes (freq: 0.009208), Other in 37 of 7182 chromosomes (freq: 0.005152), African in 44 of 24386 chromosomes (freq: 0.001804), Latino in 60 of 35410 chromosomes (freq: 0.001694), European (Finnish) in 33 of 25106 chromosomes (freq: 0.001314), Ashkenazi Jewish in 5 of 10294 chromosomes (freq: 0.000486), South Asian in 14 of 30600 chromosomes (freq: 0.000458), and East Asian in 1 of 19928 chromosomes (freq: 0.00005). Although the p.Gly62 residue is not conserved in mammals and other organisms, computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein. The variant occurs outside of the splicing consensus sequence and two of four in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign.