Genetic Variant KRTAP2-2:p.Ile77Thr (chr17-41054982-A-G) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_033032.3(KRTAP2-2):c.230T>C(p.Ile77Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0 ( 0 hom., cov: 15)

Exomes 𝑓: 0.000030 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

KRTAP2-2
NM_033032.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.963

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 Likely_benign. Variant got -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.16983727).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KRTAP2-2	NM_033032.3 link	c.230T>C	p.Ile77Thr	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.230T>C	p.Ile77Thr	missense_variant	Exon 1 of 1	6	NM_033032.3	ENSP00000381494.1		Q9BYT5

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

115638

Hom.:

Cov.:

FAILED QC

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0000299

AC:

AN:

1004524

Hom.:

Cov.:

AF XY:

0.0000280

AC XY:

AN XY:

499554

show subpopulations

Gnomad4 AFR exome

AF:

0.0000824

Gnomad4 AMR exome

AF:

0.0000359

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000579

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.000331

Gnomad4 NFE exome

AF:

0.0000172

Gnomad4 OTH exome

AF:

0.0000444

GnomAD4 genome

Data not reliable, filtered out with message: AC0;AS_VQSR

AF:

0.00

AC:

AN:

115728

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

54116

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:

0.00

Gnomad4 OTH

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Nov 14, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.230T>C (p.I77T) alteration is located in exon 1 (coding exon 1) of the KRTAP2-2 gene. This alteration results from a T to C substitution at nucleotide position 230, causing the isoleucine (I) at amino acid position 77 to be replaced by a threonine (T). 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

0.90

BayesDel_addAF

Benign

-0.023

BayesDel_noAF

Benign

-0.27

CADD

Benign

DANN

Benign

0.97

DEOGEN2

Benign

0.0048

T;.

Eigen

Uncertain

0.42

Eigen_PC

Uncertain

0.43

FATHMM_MKL

Benign

0.53

LIST_S2

Benign

0.62

T;T

M_CAP

Benign

0.0077

MetaRNN

Benign

0.17

T;T

MetaSVM

Benign

-0.79

MutationAssessor

Benign

0.81

L;.

PrimateAI

Pathogenic

0.84

PROVEAN

Benign

-0.080

N;N

REVEL

Benign

0.21

Sift

Benign

0.11

T;D

Sift4G

Benign

0.38

T;T

Vest4

0.18

MutPred

0.44

Gain of glycosylation at I77 (P = 0.036);Gain of glycosylation at I77 (P = 0.036);

MVP

0.13

ClinPred

0.25

GERP RS

4.9

Varity_R

0.074

gMVP

0.023

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.

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