17-41226917-C-T

Variant names:

• chr17-41226917-C-T
• rs923987440
• NM_031961.3:c.263C>T

Variant summary

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

The NM_031961.3(KRTAP9-2):​c.263C>T​(p.Pro88Leu) 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. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: KRTAP9-2 NM_031961.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.243

Genes affected

KRTAP9-2 (HGNC:16926): (keratin associated protein 9-2) This protein is a member of the keratin-associated protein (KAP) family. The KAP proteins form a matrix of keratin intermediate filaments which contribute to the structure of hair fibers. KAP family members appear to have unique, family-specific amino- and carboxyl-terminal regions and are subdivided into three multi-gene families according to amino acid composition: the high sulfur, the ultrahigh sulfur, and the high tyrosine/glycine KAPs. This protein is a member of the ultrahigh sulfur KAP family and the gene is localized to a cluster of KAPs at 17q12-q21. [provided by RefSeq, Jul 2008]

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=0.22339243).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KRTAP9-2	NM_031961.3	c.263C>T	p.Pro88Leu	missense_variant	Exon 1 of 1	ENST00000377721.3	NP_114167.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KRTAP9-2	ENST00000377721.3	c.263C>T	p.Pro88Leu	missense_variant	Exon 1 of 1	6	NM_031961.3	ENSP00000366950.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000399 AC: 1 AN: 250672 Hom.: 0 AF XY: 0.00000737 AC XY: 1 AN XY: 135654

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 208

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Sep 27, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.263C>T (p.P88L) alteration is located in exon 1 (coding exon 1) of the KRTAP9-2 gene. This alteration results from a C to T substitution at nucleotide position 263, causing the proline (P) at amino acid position 88 to be replaced by a leucine (L). 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	0.21
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Benign	0.18	T
Eigen	Benign	0.12
Eigen_PC	Benign	-0.036
FATHMM_MKL	Benign	0.20	N
LIST_S2	Uncertain	0.94	D
M_CAP	Benign	0.0046	T
MetaRNN	Benign	0.22	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Pathogenic	3.0	M
PrimateAI	Benign	0.24	T
PROVEAN	Pathogenic	-8.6	D
REVEL	Benign	0.059
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.91	P
Vest4		0.10
MutPred		0.59		Gain of sheet (P = 0.0061);
MVP		0.28
MPC		1.2
ClinPred		1.0	D
GERP RS		3.5
Varity_R		0.51
gMVP		0.082

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: rs923987440; hg19: chr17-39383169;