Variant 2-31177052-A-C details in Genebe, Genetics Data Aggregator

Variant summary

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

The NM_001145122.2(CAPN14):c.1946T>G(p.Leu649Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000274 in 1,551,432 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00039 ( 0 hom., cov: 34)

Exomes 𝑓: 0.00026 ( 1 hom. )

Consequence

CAPN14
NM_001145122.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.97

Variant links:

Genes affected

CAPN14 (HGNC:16664): (calpain 14) Calpains are a family of cytosolic calcium-activated cysteine proteases involved in a variety of cellular processes including apoptosis, cell division, modulation of integrin-cytoskeletal interactions, and synaptic plasticity (Dear et al., 2000 [PubMed 10964513]). CAPN14 belongs to the calpain large subunit family.[supplied by OMIM, Mar 2008]

CAPN14 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=0.117688).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CAPN14	NM_001145122.2 linkuse as main transcript	c.1946T>G	p.Leu649Trp	missense_variant	20/22	ENST00000403897.4	NP_001138594.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CAPN14	ENST00000403897.4 linkuse as main transcript	c.1946T>G	p.Leu649Trp	missense_variant	20/22	2	NM_001145122.2	ENSP00000385247	P1	A8MX76-1
CAPN14	ENST00000398824.6 linkuse as main transcript	c.*1377T>G		3_prime_UTR_variant, NMD_transcript_variant	20/22	2		ENSP00000381805

Frequencies

GnomAD3 genomes

AF:

0.000387

AC:

AN:

152264

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000338

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00131

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000941

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000279

Gnomad OTH

AF:

0.00143

GnomAD3 exomes

AF:

0.000295

AC:

AN:

156128

Hom.:

AF XY:

0.000278

AC XY:

AN XY:

82762

show subpopulations

Gnomad AFR exome

AF:

0.000253

Gnomad AMR exome

AF:

0.00101

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:

0.000216

Gnomad OTH exome

AF:

0.00137

GnomAD4 exome

AF:

0.000262

AC:

366

AN:

1399050

Hom.:

Cov.:

AF XY:

0.000243

AC XY:

168

AN XY:

690038

show subpopulations

Gnomad4 AFR exome

AF:

0.000190

Gnomad4 AMR exome

AF:

0.00106

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:

0.000270

Gnomad4 OTH exome

AF:

0.000448

GnomAD4 genome

AF:

0.000387

AC:

AN:

152382

Hom.:

Cov.:

AF XY:

0.000483

AC XY:

AN XY:

74518

show subpopulations

Gnomad4 AFR

AF:

0.000337

Gnomad4 AMR

AF:

0.00131

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0000941

Gnomad4 NFE

AF:

0.000279

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.000245

Hom.:

Bravo

AF:

0.000416

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000259

AC:

ExAC

AF:

0.0000794

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 10, 2024

The c.1946T>G (p.L649W) alteration is located in exon 20 (coding exon 19) of the CAPN14 gene. This alteration results from a T to G substitution at nucleotide position 1946, causing the leucine (L) at amino acid position 649 to be replaced by a tryptophan (W). 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

0.46

BayesDel_addAF

Benign

-0.30

BayesDel_noAF

Benign

-0.25

CADD

Benign

DANN

Benign

0.95

DEOGEN2

Benign

0.014

Eigen

Benign

0.035

Eigen_PC

Benign

-0.073

FATHMM_MKL

Uncertain

0.81

LIST_S2

Benign

0.58

M_CAP

Benign

0.042

MetaRNN

Benign

0.12

MetaSVM

Benign

-0.77

MutationAssessor

Uncertain

2.7

MutationTaster

Benign

0.60

N;N

PrimateAI

Benign

0.38

PROVEAN

Benign

-1.2

REVEL

Benign

0.26

Sift

Uncertain

0.0040

Sift4G

Uncertain

0.056

Polyphen

1.0

Vest4

0.64

MVP

0.085

ClinPred

0.054

GERP RS

2.9

Varity_R

0.090

gMVP

0.85

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