12-52904798-C-A

Position:

chr12-52904798-C-A

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_002273.4(KRT8):c.184G>T(p.Gly62Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00816 in 1,612,350 control chromosomes in the GnomAD database, including 75 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0052 ( 5 hom., cov: 32)

Exomes 𝑓: 0.0085 ( 70 hom. )

Consequence

KRT8
NM_002273.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1B:5O:1

Conservation

PhyloP100: 0.761

Variant links:

Genes affected

KRT8 (HGNC:6446): (keratin 8) This gene is a member of the type II keratin family clustered on the long arm of chromosome 12. Type I and type II keratins heteropolymerize to form intermediate-sized filaments in the cytoplasm of epithelial cells. The product of this gene typically dimerizes with keratin 18 to form an intermediate filament in simple single-layered epithelial cells. This protein plays a role in maintaining cellular structural integrity and also functions in signal transduction and cellular differentiation. Mutations in this gene cause cryptogenic cirrhosis. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Jan 2012]

KRT8 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.030593991).

BP6

Variant 12-52904798-C-A is Benign according to our data. Variant chr12-52904798-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 14630.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-52904798-C-A is described in Lovd as [Likely_benign].

BS2

High Homozygotes in GnomAd4 at 5 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
KRT8	NM_002273.4 linkuse as main transcript	c.184G>T	p.Gly62Cys	missense_variant	1/8	ENST00000692008.1	NP_002264.1
KRT8	NM_001256282.2 linkuse as main transcript	c.268G>T	p.Gly90Cys	missense_variant	2/9		NP_001243211.1
KRT8	NM_001256293.2 linkuse as main transcript	c.184G>T	p.Gly62Cys	missense_variant	2/9		NP_001243222.1
KRT8	NR_045962.2 linkuse as main transcript	n.635G>T		non_coding_transcript_exon_variant	2/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KRT8	ENST00000692008.1 linkuse as main transcript	c.184G>T	p.Gly62Cys	missense_variant	1/8		NM_002273.4	ENSP00000509398	P2	P05787-1

Frequencies

GnomAD3 genomes

AF:

0.00518

AC:

788

AN:

152208

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00200

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00164

Gnomad ASJ

AF:

0.000576

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000829

Gnomad FIN

AF:

0.000659

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00969

Gnomad OTH

AF:

0.00382

GnomAD3 exomes

AF:

0.00485

AC:

1209

AN:

249256

Hom.:

AF XY:

0.00499

AC XY:

675

AN XY:

135210

show subpopulations

Gnomad AFR exome

AF:

0.00147

Gnomad AMR exome

AF:

0.00171

Gnomad ASJ exome

AF:

0.000500

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.000458

Gnomad FIN exome

AF:

0.00129

Gnomad NFE exome

AF:

0.00932

Gnomad OTH exome

AF:

0.00525

GnomAD4 exome

AF:

0.00847

AC:

12373

AN:

1460024

Hom.:

Cov.:

AF XY:

0.00822

AC XY:

5972

AN XY:

726348

show subpopulations

Gnomad4 AFR exome

AF:

0.00135

Gnomad4 AMR exome

AF:

0.00179

Gnomad4 ASJ exome

AF:

0.000344

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000801

Gnomad4 FIN exome

AF:

0.00171

Gnomad4 NFE exome

AF:

0.0106

Gnomad4 OTH exome

AF:

0.00511

GnomAD4 genome

AF:

0.00517

AC:

788

AN:

152326

Hom.:

Cov.:

AF XY:

0.00432

AC XY:

322

AN XY:

74488

show subpopulations

Gnomad4 AFR

AF:

0.00200

Gnomad4 AMR

AF:

0.00163

Gnomad4 ASJ

AF:

0.000576

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000829

Gnomad4 FIN

AF:

0.000659

Gnomad4 NFE

AF:

0.00969

Gnomad4 OTH

AF:

0.00378

Alfa

AF:

0.00633

Hom.:

Bravo

AF:

0.00503

TwinsUK

AF:

0.00998

AC:

ALSPAC

AF:

0.0127

AC:

ESP6500AA

AF:

0.00159

AC:

ESP6500EA

AF:

0.00687

AC:

ExAC

AF:

0.00505

AC:

613

EpiCase

AF:

0.00796

EpiControl

AF:

0.00818

ClinVar

Significance: Benign/Likely benign

Submissions summary: Uncertain:1Benign:5Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4Other:1

Likely benign, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	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 (BâˆšÂºning_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. -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2023	KRT8: BS2 -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 23, 2023	- -
not provided, no classification provided	literature only	Epithelial Biology; Institute of Medical Biology, Singapore	-	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Cirrhosis, cryptogenic

Uncertain:1

Uncertain significance, no assertion criteria provided

literature only

OMIM

May 13, 2003

- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Mendelics

May 04, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.26

BayesDel_addAF

Benign

-0.15

BayesDel_noAF

Uncertain

0.030

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.71

D;D;D;.;.;T;T

Eigen

Benign

0.0040

Eigen_PC

Benign

-0.18

FATHMM_MKL

Benign

0.27

LIST_S2

Benign

0.60

.;.;T;T;T;T;T

M_CAP

Pathogenic

0.67

MetaRNN

Benign

0.031

T;T;T;T;T;T;T

MetaSVM

Uncertain

0.57

MutationAssessor

Pathogenic

3.3

M;M;M;.;.;.;.

MutationTaster

Benign

0.96

A;A;A;A;A

PrimateAI

Benign

0.35

PROVEAN

Pathogenic

-6.2

D;D;D;D;D;D;D

REVEL

Uncertain

0.53

Sift

Uncertain

0.0020

D;D;D;D;D;D;D

Sift4G

Pathogenic

0.0

D;D;D;D;.;.;D

Polyphen

1.0

D;D;D;.;.;.;.

Vest4

0.30

MVP

0.95

MPC

1.4

ClinPred

0.11

GERP RS

1.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.56

gMVP

0.93

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over