17-41065571-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_033184.4(KRTAP2-4):​c.275G>A​(p.Cys92Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000753 in 1,460,650 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000071 ( 0 hom., cov: 30)
Exomes 𝑓: 0.0000076 ( 0 hom. )

Consequence

KRTAP2-4
NM_033184.4 missense

Scores

2
9
6

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.43
Variant links:
Genes affected
KRTAP2-4 (HGNC:18891): (keratin associated protein 2-4) 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 high sulfur KAP family and the gene is localized to a cluster of KAPs at 17q12-q21. [provided by RefSeq, Jul 2008]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.29927212).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
KRTAP2-4NM_033184.4 linkc.275G>A p.Cys92Tyr missense_variant Exon 1 of 1 ENST00000394015.3 NP_149440.1 P0C7H8Q9BYR9

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
KRTAP2-4ENST00000394015.3 linkc.275G>A p.Cys92Tyr missense_variant Exon 1 of 1 6 NM_033184.4 ENSP00000377583.2 Q9BYR9

Frequencies

GnomAD3 genomes
AF:
0.00000709
AC:
1
AN:
141060
Hom.:
0
Cov.:
30
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000163
Gnomad OTH
AF:
0.00
GnomAD4 exome
AF:
0.00000758
AC:
10
AN:
1319590
Hom.:
0
Cov.:
31
AF XY:
0.0000123
AC XY:
8
AN XY:
651058
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000976
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.00000709
AC:
1
AN:
141060
Hom.:
0
Cov.:
30
AF XY:
0.00
AC XY:
0
AN XY:
68946
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000163
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000151

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Dec 01, 2022
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.275G>A (p.C92Y) alteration is located in exon 1 (coding exon 1) of the KRTAP2-4 gene. This alteration results from a G to A substitution at nucleotide position 275, causing the cysteine (C) at amino acid position 92 to be replaced by a tyrosine (Y). 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
Pathogenic
0.72
BayesDel_addAF
Pathogenic
0.18
D
BayesDel_noAF
Uncertain
0.020
CADD
Uncertain
26
DANN
Uncertain
1.0
DEOGEN2
Benign
0.022
T
Eigen
Uncertain
0.48
Eigen_PC
Uncertain
0.52
FATHMM_MKL
Uncertain
0.92
D
M_CAP
Benign
0.016
T
MetaRNN
Benign
0.30
T
MetaSVM
Uncertain
-0.18
T
PrimateAI
Uncertain
0.76
T
PROVEAN
Uncertain
-3.6
D
REVEL
Benign
0.21
Sift
Uncertain
0.014
D
Sift4G
Benign
0.092
T
Vest4
0.41
MutPred
0.43
Loss of catalytic residue at P91 (P = 0.0031);
MVP
0.17
MPC
2.0
ClinPred
0.95
D
GERP RS
5.6
Varity_R
0.36
gMVP
0.12

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
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.

Other links and lift over

dbSNP: rs201193479; hg19: chr17-39221823; API