17-41516161-C-G

Variant names:

• chr17-41516161-C-G
• NM_002275.4:c.843G>C

Variant summary

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

The NM_002275.4(KRT15):​c.843G>C​(p.Gln281His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: KRT15 NM_002275.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.606

Genes affected

KRT15 (HGNC:6421): (keratin 15) The protein encoded by this gene is a member of the keratin gene family. The keratins are intermediate filament proteins responsible for the structural integrity of epithelial cells and are subdivided into cytokeratins and hair keratins. Most of the type I cytokeratins consist of acidic proteins which are arranged in pairs of heterotypic keratin chains and are clustered in a region on chromosome 17q21.2. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KRT15	NM_002275.4	c.843G>C	p.Gln281His	missense_variant	Exon 4 of 8	ENST00000254043.8	NP_002266.3
KRT15	XM_011524784.4	c.864G>C	p.Gln288His	missense_variant	Exon 4 of 8		XP_011523086.1
KRT15	XM_017024614.3	c.864G>C	p.Gln288His	missense_variant	Exon 4 of 8		XP_016880103.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KRT15	ENST00000254043.8	c.843G>C	p.Gln281His	missense_variant	Exon 4 of 8	1	NM_002275.4	ENSP00000254043.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 17, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.843G>C (p.Q281H) alteration is located in exon 4 (coding exon 4) of the KRT15 gene. This alteration results from a G to C substitution at nucleotide position 843, causing the glutamine (Q) at amino acid position 281 to be replaced by a histidine (H). 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	Uncertain	0.35
BayesDel_addAF	Benign	0.0038	T
BayesDel_noAF	Benign	-0.23
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.58	D;D;D;.
Eigen	Uncertain	0.34
Eigen_PC	Uncertain	0.25
FATHMM_MKL	Benign	0.64	D
LIST_S2	Uncertain	0.88	.;D;D;D
M_CAP	Benign	0.048	D
MetaRNN	Uncertain	0.68	D;D;D;D
MetaSVM	Uncertain	0.15	D
MutationAssessor	Uncertain	2.3	M;.;M;.
PrimateAI	Uncertain	0.57	T
PROVEAN	Pathogenic	-4.6	D;D;D;D
REVEL	Pathogenic	0.65
Sift	Uncertain	0.023	D;T;D;T
Sift4G	Benign	0.084	T;T;T;.
Polyphen		0.93	P;D;P;.
Vest4		0.25
MutPred		0.75		Loss of disorder (P = 0.1356);.;Loss of disorder (P = 0.1356);.;
MVP		0.86
MPC		0.51
ClinPred		0.99	D
GERP RS		2.5
Varity_R		0.44
gMVP		0.60

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr17-39672413;