Genetic Variant NM_173853.4:c.337C>T (chr2-27443137-C-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

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

The NM_173853.4(KRTCAP3):c.337C>T(p.Leu113Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000124 in 1,614,042 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000013 ( 0 hom. )

Consequence

KRTCAP3
NM_173853.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.45

Variant links:

Genes affected

KRTCAP3 (HGNC:28943): (keratinocyte associated protein 3) Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

KRTCAP3 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KRTCAP3	NM_173853.4 link	c.337C>T	p.Leu113Phe	missense_variant	Exon 4 of 7	ENST00000288873.7	NP_776252.2	Q53RY4-1
KRTCAP3	NM_001168364.2 link	c.337C>T	p.Leu113Phe	missense_variant	Exon 4 of 7		NP_001161836.1	Q53RY4-1
KRTCAP3	NM_001321325.2 link	c.337C>T	p.Leu113Phe	missense_variant	Exon 4 of 7		NP_001308254.1	Q53RY4-1
KRTCAP3	XM_047443704.1 link	c.337C>T	p.Leu113Phe	missense_variant	Exon 4 of 6		XP_047299660.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KRTCAP3	ENST00000288873.7 link	c.337C>T	p.Leu113Phe	missense_variant	Exon 4 of 7	1	NM_173853.4	ENSP00000288873.3		Q53RY4-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152172

Hom.:

Cov.:

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000130

AC:

AN:

1461870

Hom.:

Cov.:

AF XY:

0.00000963

AC XY:

AN XY:

727236

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:

0.0000171

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152172

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74338

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:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Aug 30, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.337C>T (p.L113F) alteration is located in exon 4 (coding exon 4) of the KRTCAP3 gene. This alteration results from a C to T substitution at nucleotide position 337, causing the leucine (L) at amino acid position 113 to be replaced by a phenylalanine (F). 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

Uncertain

0.41

BayesDel_addAF

Uncertain

0.042

BayesDel_noAF

Benign

-0.18

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.32

T;T;.

Eigen

Uncertain

0.55

Eigen_PC

Uncertain

0.52

FATHMM_MKL

Uncertain

0.92

LIST_S2

Uncertain

0.89

D;.;D

M_CAP

Benign

0.072

MetaRNN

Uncertain

0.48

T;T;T

MetaSVM

Benign

-0.39

MutationAssessor

Uncertain

2.3

M;M;.

PrimateAI

Uncertain

0.68

PROVEAN

Uncertain

-3.6

D;D;D

REVEL

Uncertain

0.42

Sift

Pathogenic

0.0

D;D;D

Sift4G

Uncertain

0.0050

D;D;D

Polyphen

0.99

D;D;.

Vest4

0.44

MutPred

0.62

Gain of catalytic residue at L113 (P = 0.0441);Gain of catalytic residue at L113 (P = 0.0441);.;

MVP

0.66

MPC

0.52

ClinPred

1.0

GERP RS

4.9

Varity_R

0.82

gMVP

0.78

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