dbSNP rs1939128751: KRT76:p.Ser635Arg (chr12-52768725-G-C) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_015848.4(KRT76):c.1905C>G(p.Ser635Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000901 in 1,442,442 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.0000090 ( 0 hom. )

Consequence

KRT76
NM_015848.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.68

Publications

0 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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.07816246).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KRT76	NM_015848.4 link	c.1905C>G	p.Ser635Arg	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.1905C>G	p.Ser635Arg	missense_variant	Exon 9 of 9	1	NM_015848.4	ENSP00000330101.2		Q01546

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000901

AC:

AN:

1442442

Hom.:

Cov.:

AF XY:

0.00000841

AC XY:

AN XY:

713212

show subpopulations

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

African (AFR)

AF:

0.00

AC:

AN:

33196

American (AMR)

AF:

0.00

AC:

AN:

44298

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25612

East Asian (EAS)

AF:

0.00

AC:

AN:

39124

South Asian (SAS)

AF:

0.00

AC:

AN:

85222

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53050

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5708

European-Non Finnish (NFE)

AF:

0.0000119

AC:

AN:

1096790

Other (OTH)

AF:

0.00

AC:

AN:

59442

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000181), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.398

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Apr 19, 2025

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.1905C>G (p.S635R) alteration is located in exon 9 (coding exon 9) of the KRT76 gene. This alteration results from a C to G substitution at nucleotide position 1905, causing the serine (S) at amino acid position 635 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Benign

-0.14

BayesDel_noAF

Benign

-0.43

CADD

Benign

(source)

DANN

Benign

0.46

DEOGEN2

Benign

0.083

Eigen

Benign

-0.79

Eigen_PC

Benign

-0.67

FATHMM_MKL

Uncertain

0.91

LIST_S2

Benign

0.24

M_CAP

Benign

0.014

MetaRNN

Benign

0.078

MetaSVM

Benign

-0.87

MutationAssessor

Benign

0.0

PhyloP100

4.7

PrimateAI

Benign

0.30

PROVEAN

Benign

-0.71

REVEL

Benign

0.25

Sift

Benign

1.0

Sift4G

Benign

0.14

Polyphen

0.0

Vest4

0.11

MutPred

0.28

Loss of phosphorylation at S635 (P = 0.0038);

MVP

0.37

MPC

0.055

ClinPred

0.030

GERP RS

3.7

Varity_R

0.066

gMVP

0.40

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

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rs1939128751

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