Genetic Variant KRT76:p.Gly540Ser (chr12-52769012-C-T) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 2P and 6B. PM2BP4_StrongBP6_Moderate

The NM_015848.4(KRT76):c.1618G>A(p.Gly540Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000136 in 734,976 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.000014 ( 0 hom. )

Consequence

KRT76
NM_015848.4 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: -2.44

Publications

1 publications found

Variant links:

Genes affected

KRT76 (HGNC:24430): (keratin 76) Keratins are intermediate filament proteins responsible for the structural integrity of epithelial cells and are subdivided into epithelial keratins and hair keratins. The type II keratins are clustered in a region of chromosome 12q13. [provided by RefSeq, Jun 2009]

KRT76 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.036901712).

BP6

Variant 12-52769012-C-T is Benign according to our data. Variant chr12-52769012-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 2348985.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KRT76	NM_015848.4 link	c.1618G>A	p.Gly540Ser	missense_variant	Exon 9 of 9	ENST00000332411.2	NP_056932.2	Q01546

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KRT76	ENST00000332411.2 link	c.1618G>A	p.Gly540Ser	missense_variant	Exon 9 of 9	1	NM_015848.4	ENSP00000330101.2		Q01546

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.0000189

AC:

AN:

158976

AF XY:

0.0000238

show subpopulations

Gnomad AFR exome

AF:

0.000114

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000162

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000136

AC:

AN:

734976

Hom.:

Cov.:

AF XY:

0.0000104

AC XY:

AN XY:

386392

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.000220

AC:

AN:

18216

American (AMR)

AF:

0.00

AC:

AN:

34990

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

20998

East Asian (EAS)

AF:

0.00

AC:

AN:

32788

South Asian (SAS)

AF:

0.0000151

AC:

AN:

66436

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49168

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4400

European-Non Finnish (NFE)

AF:

0.0000106

AC:

AN:

471904

Other (OTH)

AF:

0.00

AC:

AN:

36076

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000113), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.365

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000260

Hom.:

ExAC

AF:

0.000147

AC:

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Benign:1

Aug 17, 2022

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.071

BayesDel_addAF

Uncertain

0.013

BayesDel_noAF

Benign

-0.22

CADD

Benign

0.029

(source)

DANN

Benign

0.25

DEOGEN2

Benign

0.0028

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.0065

LIST_S2

Benign

0.28

M_CAP

Benign

0.015

MetaRNN

Benign

0.037

MetaSVM

Benign

-0.49

MutationAssessor

Benign

0.34

PhyloP100

-2.4

PrimateAI

Benign

0.37

PROVEAN

Benign

-1.8

REVEL

Uncertain

0.30

Sift

Benign

0.42

Sift4G

Benign

0.21

Polyphen

0.034

Vest4

0.12

MVP

0.19

MPC

0.050

ClinPred

0.0094

GERP RS

-1.6

Varity_R

0.033

gMVP

0.39

Mutation Taster

=99/1

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

12-52769012-C-T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over