17-40818895-G-T

Position:

• chr17-40818895-G-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_000421.5(KRT10):​c.1640C>A​(p.Ser547Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0129 in 1,258,874 control chromosomes in the GnomAD database, including 39 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 Benign (★). Synonymous variant affecting the same amino acid position (i.e. SG547SAAAAAPAADTAAAAAPAADR?) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0069 (0 hom., cov: 24)
  • Exomes 𝑓: 0.013 (39 hom.)
• Consequence: KRT10 NM_000421.5 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.91

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]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0038961768).
• BP6: Variant 17-40818895-G-T is Benign according to our data. Variant chr17-40818895-G-T is described in ClinVar as [Benign]. Clinvar id is 1601794.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00689 (598/86842) while in subpopulation EAS AF= 0.0307 (68/2214). AF 95% confidence interval is 0.0249. There are 0 homozygotes in gnomad4. There are 269 alleles in male gnomad4 subpopulation. Median coverage is 24. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 39 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KRT10	NM_000421.5	c.1640C>A	p.Ser547Tyr	missense_variant	7/8	ENST00000269576.6	NP_000412.4
KRT10	NM_001379366.1	c.1640C>A	p.Ser547Tyr	missense_variant	7/8		NP_001366295.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KRT10	ENST00000269576.6	c.1640C>A	p.Ser547Tyr	missense_variant	7/8	1	NM_000421.5	ENSP00000269576	P2
KRT10	ENST00000635956.2	c.1640C>A	p.Ser547Tyr	missense_variant	7/8	2		ENSP00000490524	A2

Frequencies

GnomAD3 genomes AF: 0.00690 AC: 599 AN: 86752 Hom.: 0 Cov.: 24

Gnomad AFR AF: 0.0145

Gnomad AMI AF: 0.00316

Gnomad AMR AF: 0.00208

Gnomad ASJ AF: 0.00392

Gnomad EAS AF: 0.0307

Gnomad SAS AF: 0.0109

Gnomad FIN AF: 0.00517

Gnomad MID AF: 0.00685

Gnomad NFE AF: 0.00439

Gnomad OTH AF: 0.0103

GnomAD3 exomes AF: 0.0107 AC: 1242 AN: 116164 Hom.: 12 AF XY: 0.0111 AC XY: 724 AN XY: 65198

Gnomad AFR exome AF: 0.0408

Gnomad AMR exome AF: 0.00265

Gnomad ASJ exome AF: 0.00622

Gnomad EAS exome AF: 0.0358

Gnomad SAS exome AF: 0.0128

Gnomad FIN exome AF: 0.0105

Gnomad NFE exome AF: 0.00986

Gnomad OTH exome AF: 0.00844

GnomAD4 exome AF: 0.0133 AC: 15594 AN: 1172032 Hom.: 39 Cov.: 30 AF XY: 0.0129 AC XY: 7451 AN XY: 576734

Gnomad4 AFR exome AF: 0.0313

Gnomad4 AMR exome AF: 0.00639

Gnomad4 ASJ exome AF: 0.0102

Gnomad4 EAS exome AF: 0.0162

Gnomad4 SAS exome AF: 0.0168

Gnomad4 FIN exome AF: 0.00429

Gnomad4 NFE exome AF: 0.0131

Gnomad4 OTH exome AF: 0.0148

GnomAD4 genome AF: 0.00689 AC: 598 AN: 86842 Hom.: 0 Cov.: 24 AF XY: 0.00635 AC XY: 269 AN XY: 42356

Gnomad4 AFR AF: 0.0143

Gnomad4 AMR AF: 0.00208

Gnomad4 ASJ AF: 0.00392

Gnomad4 EAS AF: 0.0307

Gnomad4 SAS AF: 0.0109

Gnomad4 FIN AF: 0.00517

Gnomad4 NFE AF: 0.00439

Gnomad4 OTH AF: 0.0102

ExAC AF: 0.0133 AC: 1360

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 24, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.087	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	2.7
DANN	Benign	0.64
DEOGEN2	Benign	0.019	T;T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.25	T;T
MetaRNN	Benign	0.0039	T;T
MetaSVM	Benign	-0.56	T
MutationAssessor	Benign	1.2	.;L
MutationTaster	Benign	1.0	N
PrimateAI	Pathogenic	0.79	T
PROVEAN	Benign	0.070	.;N
REVEL	Benign	0.18
Sift	Pathogenic	0.0	.;D
Sift4G	Benign	0.77	.;T
Polyphen		0.0010	.;B
Vest4		0.077
MPC		0.54
ClinPred		0.017	T
GERP RS		-0.18
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.051
gMVP		0.64

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

Other links and lift over

dbSNP: rs752817112; hg19: chr17-38975147; COSMIC: COSV54088315; COSMIC: COSV54088315;