Genetic Variant KRTAP2-4:p.Cys80Ser (chr17-41065608-A-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_033184.4(KRTAP2-4):c.238T>A(p.Cys80Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000332 in 150,614 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 0.000033 ( 0 hom., cov: 30)

Exomes 𝑓: 0.0000029 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

KRTAP2-4
NM_033184.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.50

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]

KRTAP2-4 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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=0.17493805).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KRTAP2-4	NM_033184.4 link	c.238T>A	p.Cys80Ser	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
KRTAP2-4	ENST00000394015.3 link	c.238T>A	p.Cys80Ser	missense_variant	Exon 1 of 1	6	NM_033184.4	ENSP00000377583.2		Q9BYR9

Frequencies

GnomAD3 genomes

AF:

0.0000332

AC:

AN:

150494

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000243

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:

0.0000952

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000446

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000383

AC:

AN:

130538

Hom.:

AF XY:

0.0000426

AC XY:

AN XY:

70440

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000990

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00000294

AC:

AN:

1361000

Hom.:

Cov.:

AF XY:

0.00000299

AC XY:

AN XY:

669266

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:

0.0000128

Gnomad4 FIN exome

AF:

0.0000589

Gnomad4 NFE exome

AF:

9.42e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000332

AC:

AN:

150614

Hom.:

Cov.:

AF XY:

0.0000272

AC XY:

AN XY:

73586

show subpopulations

Gnomad4 AFR

AF:

0.0000242

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0000952

Gnomad4 NFE

AF:

0.0000446

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000671

Hom.:

ExAC

AF:

0.0000932

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jun 07, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.238T>A (p.C80S) alteration is located in exon 1 (coding exon 1) of the KRTAP2-4 gene. This alteration results from a T to A substitution at nucleotide position 238, causing the cysteine (C) at amino acid position 80 to be replaced by a serine (S). 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

0.71

BayesDel_addAF

Uncertain

0.11

BayesDel_noAF

Uncertain

-0.080

CADD

Benign

DANN

Benign

0.94

DEOGEN2

Benign

0.017

Eigen

Uncertain

0.39

Eigen_PC

Uncertain

0.43

FATHMM_MKL

Uncertain

0.77

M_CAP

Benign

0.016

MetaRNN

Benign

0.17

MetaSVM

Benign

-0.29

PrimateAI

Uncertain

0.74

PROVEAN

Uncertain

-3.6

REVEL

Benign

0.21

Sift

Benign

0.12

Sift4G

Uncertain

0.049

Vest4

0.45

MutPred

0.46

Gain of glycosylation at T78 (P = 0.0448);

MVP

0.17

MPC

1.7

ClinPred

0.23

GERP RS

5.5

Varity_R

0.29

gMVP

0.079

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over