Genetic Variant KRTAP2-2:p.Pro22Arg (chr17-41055147-G-C) – 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_033032.3(KRTAP2-2):c.65C>G(p.Pro22Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0000604 in 1,374,182 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: 𝑓 0.000056 ( 0 hom., cov: 19)

Exomes 𝑓: 0.000061 ( 0 hom. )

Consequence

KRTAP2-2
NM_033032.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.18

Variant links:

Genes affected

KRTAP2-2 (HGNC:18905): (keratin associated protein 2-2) Predicted to be located in cytosol. [provided by Alliance of Genome Resources, Apr 2022]

KRTAP2-2 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=0.17038432).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KRTAP2-2	NM_033032.3 link	c.65C>G	p.Pro22Arg	missense_variant	Exon 1 of 1	ENST00000398477.1	NP_149021.2	Q9BYT5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KRTAP2-2	ENST00000398477.1 link	c.65C>G	p.Pro22Arg	missense_variant	Exon 1 of 1	6	NM_033032.3	ENSP00000381494.1		Q9BYT5

Frequencies

GnomAD3 genomes

AF:

0.0000563

AC:

AN:

142092

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000528

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000714

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:

0.0000768

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000106

AC:

AN:

75534

Hom.:

AF XY:

0.000130

AC XY:

AN XY:

38444

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000198

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000109

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000103

Gnomad OTH exome

AF:

0.000405

GnomAD4 exome

AF:

0.0000609

AC:

AN:

1231978

Hom.:

Cov.:

AF XY:

0.0000630

AC XY:

AN XY:

603136

show subpopulations

Gnomad4 AFR exome

AF:

0.0000730

Gnomad4 AMR exome

AF:

0.000161

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000574

Gnomad4 SAS exome

AF:

0.0000927

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000565

Gnomad4 OTH exome

AF:

0.000115

GnomAD4 genome

AF:

0.0000563

AC:

AN:

142204

Hom.:

Cov.:

AF XY:

0.0000581

AC XY:

AN XY:

68870

show subpopulations

Gnomad4 AFR

AF:

0.0000526

Gnomad4 AMR

AF:

0.0000713

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000768

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000193

Hom.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Feb 05, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.65C>G (p.P22R) alteration is located in exon 1 (coding exon 1) of the KRTAP2-2 gene. This alteration results from a C to G substitution at nucleotide position 65, causing the proline (P) at amino acid position 22 to be replaced by an arginine (R). 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

0.28

BayesDel_addAF

Benign

-0.037

BayesDel_noAF

Benign

-0.29

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.045

T;.

Eigen

Pathogenic

0.68

Eigen_PC

Uncertain

0.64

FATHMM_MKL

Uncertain

0.88

LIST_S2

Benign

0.71

T;T

M_CAP

Benign

0.0083

MetaRNN

Benign

0.17

T;T

MetaSVM

Benign

-0.68

MutationAssessor

Pathogenic

3.1

M;.

PrimateAI

Uncertain

0.69

PROVEAN

Pathogenic

-6.2

D;D

REVEL

Uncertain

0.31

Sift

Uncertain

0.0010

D;D

Sift4G

Uncertain

0.0020

D;D

Vest4

0.32

MutPred

0.57

Loss of catalytic residue at P22 (P = 0.1203);Loss of catalytic residue at P22 (P = 0.1203);

MVP

0.43

ClinPred

0.27

GERP RS

5.2

Varity_R

0.68

gMVP

0.091

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

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