Variant 17-40978217-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001389244.1(KRT40):c.1276G>A(p.Val426Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000799 in 1,613,568 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000072 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000081 ( 1 hom. )

Consequence

KRT40
NM_001389244.1 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.29

Variant links:

Genes affected

KRT40 (HGNC:26707): (keratin 40) This gene encodes a member of the type I (acidic) keratin family, which belongs to the superfamily of intermediate filament (IF) proteins. Keratins are heteropolymeric structural proteins which form the intermediate filament. These filaments, along with actin microfilaments and microtubules, compose the cytoskeleton of epithelial cells. The type I keratin genes are clustered in a region of chromosome 17q12-q21. [provided by RefSeq, Jul 2009]

KRT40 links:

LOC107985072 (HGNC:):

LOC107985072 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.0154803395).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KRT40	NM_001389244.1 linkuse as main transcript	c.1276G>A	p.Val426Ile	missense_variant	7/7	ENST00000377755.9	NP_001376173.1
LOC107985072	XR_001752886.2 linkuse as main transcript	n.189-2232C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
KRT40	ENST00000377755.9 linkuse as main transcript	c.1276G>A	p.Val426Ile	missense_variant	7/7	1	NM_001389244.1	ENSP00000366984	P1
KRT40	ENST00000398486.2 linkuse as main transcript	c.1276G>A	p.Val426Ile	missense_variant	9/9	1		ENSP00000381500	P1
KRT40	ENST00000684280.1 linkuse as main transcript	c.1276G>A	p.Val426Ile	missense_variant	9/9			ENSP00000506768	P1
KRT40	ENST00000461923.5 linkuse as main transcript	c.*738G>A		3_prime_UTR_variant, NMD_transcript_variant	9/9	2		ENSP00000434458

Frequencies

GnomAD3 genomes

AF:

0.0000723

AC:

AN:

152164

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000393

Gnomad ASJ

AF:

0.00144

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000148

AC:

AN:

249478

Hom.:

AF XY:

0.000111

AC XY:

AN XY:

135346

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000579

Gnomad ASJ exome

AF:

0.00308

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000177

Gnomad OTH exome

AF:

0.000330

GnomAD4 exome

AF:

0.0000807

AC:

118

AN:

1461404

Hom.:

Cov.:

AF XY:

0.0000798

AC XY:

AN XY:

727084

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000671

Gnomad4 ASJ exome

AF:

0.00356

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000720

Gnomad4 OTH exome

AF:

0.000232

GnomAD4 genome

AF:

0.0000723

AC:

AN:

152164

Hom.:

Cov.:

AF XY:

0.0000807

AC XY:

AN XY:

74324

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000393

Gnomad4 ASJ

AF:

0.00144

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000293

Hom.:

Bravo

AF:

0.000106

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000120

AC:

ExAC

AF:

0.0000992

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 21, 2023

The c.1276G>A (p.V426I) alteration is located in exon 9 (coding exon 7) of the KRT40 gene. This alteration results from a G to A substitution at nucleotide position 1276, causing the valine (V) at amino acid position 426 to be replaced by an isoleucine (I). 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

0.089

BayesDel_addAF

Benign

-0.20

BayesDel_noAF

Benign

-0.35

CADD

Benign

DANN

Benign

0.83

DEOGEN2

Benign

0.0061

T;T

Eigen

Benign

-0.65

Eigen_PC

Benign

-0.51

FATHMM_MKL

Benign

0.59

M_CAP

Benign

0.012

MetaRNN

Benign

0.015

T;T

MetaSVM

Benign

-0.88

MutationAssessor

Benign

1.9

L;L

MutationTaster

Benign

0.99

N;N

PrimateAI

Benign

0.34

PROVEAN

Benign

-0.34

N;N

REVEL

Benign

0.11

Sift

Benign

0.44

T;T

Sift4G

Benign

0.49

T;T

Polyphen

0.0050

B;B

Vest4

0.16

MVP

0.43

MPC

0.085

ClinPred

0.025

GERP RS

4.2

Varity_R

0.040

gMVP

0.26

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