17-40818899-T-A

Variant names:

• chr17-40818899-T-A
• rs1217847176
• NM_000421.5:c.1636A>T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000421.5(KRT10):​c.1636A>T​(p.Ser546Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 23)
• Consequence: KRT10 NM_000421.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.619

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-AS1 (HGNC:28305): (KRT10 antisense RNA 1) Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.17863011).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KRT10	NM_000421.5	c.1636A>T	p.Ser546Cys	missense_variant	Exon 7 of 8	ENST00000269576.6	NP_000412.4
KRT10	NM_001379366.1	c.1636A>T	p.Ser546Cys	missense_variant	Exon 7 of 8		NP_001366295.1
KRT10-AS1	NR_160887.1	n.-246T>A		upstream_gene_variant
KRT10-AS1	NR_160888.1	n.-246T>A		upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KRT10	ENST00000269576.6	c.1636A>T	p.Ser546Cys	missense_variant	Exon 7 of 8	1	NM_000421.5	ENSP00000269576.5

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 23

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Uncertain	0.039	T
BayesDel_noAF	Benign	-0.18
CADD	Benign	17
DANN	Benign	0.66
DEOGEN2	Benign	0.072	T;T
Eigen	Benign	-0.75
Eigen_PC	Benign	-0.85
FATHMM_MKL	Benign	0.22	N
LIST_S2	Benign	0.22	T;T
M_CAP	Uncertain	0.12	D
MetaRNN	Benign	0.18	T;T
MetaSVM	Benign	-0.53	T
MutationAssessor	Uncertain	2.2	.;M
PrimateAI	Uncertain	0.76	T
PROVEAN	Benign	-0.19	.;N
REVEL	Uncertain	0.29
Sift	Pathogenic	0.0	.;D
Sift4G	Uncertain	0.016	.;D
Polyphen		0.95	.;P
Vest4		0.27
MutPred		0.35		.;Loss of phosphorylation at S546 (P = 4e-04);
MVP		0.75
MPC		0.41
ClinPred		0.36	T
GERP RS		1.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.1
Varity_R		0.089
gMVP		0.48

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: rs1217847176; hg19: chr17-38975151;