17-40818899-T-C

Variant summary

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

The NM_000421.5(KRT10):c.1636A>G(p.Ser546Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00047 in 1,180,316 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S546R) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00029 ( 0 hom., cov: 23)

Exomes 𝑓: 0.00047 ( 1 hom. )

Failed GnomAD Quality Control

Consequence

KRT10
NM_000421.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.619

Variant links:

Genes affected

KRT10 (HGNC:6413): (keratin 10) This gene encodes a member of the type I (acidic) cytokeratin 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. Mutations in this gene are associated with epidermolytic hyperkeratosis. This gene is located within a cluster of keratin family members on chromosome 17q21. [provided by RefSeq, Jul 2008]

KRT10 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=0.0028027594).

BP6

Variant 17-40818899-T-C is Benign according to our data. Variant chr17-40818899-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 1223538.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High Homozygotes in GnomAdExome at 2 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KRT10	NM_000421.5 linkuse as main transcript	c.1636A>G	p.Ser546Gly	missense_variant	7/8	ENST00000269576.6
KRT10	NM_001379366.1 linkuse as main transcript	c.1636A>G	p.Ser546Gly	missense_variant	7/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KRT10	ENST00000269576.6 linkuse as main transcript	c.1636A>G	p.Ser546Gly	missense_variant	7/8	1	NM_000421.5	P2
KRT10	ENST00000635956.2 linkuse as main transcript	c.1636A>G	p.Ser546Gly	missense_variant	7/8	2		A2

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

85374

Hom.:

Cov.:

FAILED QC

Gnomad AFR

AF:

0.000848

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000101

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000887

Gnomad SAS

AF:

0.000835

Gnomad FIN

AF:

0.000163

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000133

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00712

AC:

763

AN:

107222

Hom.:

AF XY:

0.00737

AC XY:

445

AN XY:

60416

show subpopulations

Gnomad AFR exome

AF:

0.0282

Gnomad AMR exome

AF:

0.00160

Gnomad ASJ exome

AF:

0.00459

Gnomad EAS exome

AF:

0.0197

Gnomad SAS exome

AF:

0.00890

Gnomad FIN exome

AF:

0.00868

Gnomad NFE exome

AF:

0.00666

Gnomad OTH exome

AF:

0.00576

GnomAD4 exome

AF:

0.000470

AC:

555

AN:

1180316

Hom.:

Cov.:

AF XY:

0.000583

AC XY:

338

AN XY:

579926

show subpopulations

Gnomad4 AFR exome

AF:

0.00169

Gnomad4 AMR exome

AF:

0.00145

Gnomad4 ASJ exome

AF:

0.00112

Gnomad4 EAS exome

AF:

0.00176

Gnomad4 SAS exome

AF:

0.00254

Gnomad4 FIN exome

AF:

0.000943

Gnomad4 NFE exome

AF:

0.000232

Gnomad4 OTH exome

AF:

0.000525

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.000293

AC:

AN:

85466

Hom.:

Cov.:

AF XY:

0.000168

AC XY:

AN XY:

41602

show subpopulations

Gnomad4 AFR

AF:

0.000844

Gnomad4 AMR

AF:

0.000101

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000888

Gnomad4 SAS

AF:

0.000835

Gnomad4 FIN

AF:

0.000163

Gnomad4 NFE

AF:

0.000133

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.00422

Hom.:

ExAC

AF:

0.0112

AC:

1117

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Oct 19, 2022	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 05, 2019	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.079

BayesDel_addAF

Benign

-0.091

BayesDel_noAF

Benign

-0.37

Cadd

Benign

9.4

Dann

Benign

0.48

DEOGEN2

Benign

0.030

T;T

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.084

LIST_S2

Benign

0.21

T;T

MetaRNN

Benign

0.0028

T;T

MetaSVM

Benign

-0.81

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.73

Polyphen

0.0

.;B

Vest4

0.19

MutPred

0.30

.;Loss of phosphorylation at S546 (P = 4e-04);

MPC

0.38

ClinPred

0.018

GERP RS

1.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.1

Varity_R

0.080

gMVP

0.25

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