Variant 19-36141100-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4BS2

The NM_001749.4(CAPNS1):c.89G>A(p.Gly30Glu) variant causes a missense change. The variant allele was found at a frequency of 0.000949 in 1,451,508 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00067 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00098 ( 2 hom. )

Consequence

CAPNS1
NM_001749.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.15

Variant links:

Genes affected

CAPNS1 (HGNC:1481): (calpain small subunit 1) This gene is a member of the calpain small subunit family. Calpains are calcium-dependent cysteine proteinases that are widely distributed in mammalian cells. Calpains operate as heterodimers, comprising a specific large catalytic subunit (calpain 1 subunit in Calpain I, and calpain 2 subunit in Calpain II), and a common small regulatory subunit encoded by this gene. This encoded protein is essential for the stability and function of both calpain heterodimers, whose proteolytic activities influence various cellular functions including apoptosis, proliferation, migration, adhesion, and autophagy. Calpains have been implicated in neurodegenerative processes, such as myotonic dystrophy. A pseudogene of this gene has been defined on chromosome 1. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Oct 2014]

CAPNS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.26861507).

BS2

High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CAPNS1	NM_001749.4 linkuse as main transcript	c.89G>A	p.Gly30Glu	missense_variant	2/11	ENST00000246533.8	NP_001740.1	P04632

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CAPNS1	ENST00000246533.8 linkuse as main transcript	c.89G>A	p.Gly30Glu	missense_variant	2/11	1	NM_001749.4	ENSP00000246533.2		P04632

Frequencies

GnomAD3 genomes

AF:

0.000669

AC:

100

AN:

149540

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000320

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000200

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:

0.00125

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000440

AC:

AN:

72654

Hom.:

AF XY:

0.000532

AC XY:

AN XY:

41360

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000175

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:

0.00125

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000982

AC:

1278

AN:

1301968

Hom.:

Cov.:

AF XY:

0.000997

AC XY:

639

AN XY:

641220

show subpopulations

Gnomad4 AFR exome

AF:

0.000116

Gnomad4 AMR exome

AF:

0.0000874

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:

0.00120

Gnomad4 OTH exome

AF:

0.000617

GnomAD4 genome

AF:

0.000669

AC:

100

AN:

149540

Hom.:

Cov.:

AF XY:

0.000548

AC XY:

AN XY:

72968

show subpopulations

Gnomad4 AFR

AF:

0.000320

Gnomad4 AMR

AF:

0.000200

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00125

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000808

Hom.:

Bravo

AF:

0.000688

ExAC

AF:

0.000220

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

Aug 16, 2021

The c.89G>A (p.G30E) alteration is located in exon 2 (coding exon 1) of the CAPNS1 gene. This alteration results from a G to A substitution at nucleotide position 89, causing the glycine (G) at amino acid position 30 to be replaced by a glutamic acid (E). 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

0.50

BayesDel_addAF

Benign

-0.12

BayesDel_noAF

Uncertain

0.020

CADD

Uncertain

DANN

Benign

0.97

DEOGEN2

Benign

0.30

T;T;T;.;T;T;T;.;T

Eigen

Uncertain

0.26

Eigen_PC

Uncertain

0.36

FATHMM_MKL

Uncertain

0.94

LIST_S2

Benign

0.71

.;T;T;T;T;.;T;T;.

M_CAP

Pathogenic

0.86

MetaRNN

Benign

0.27

T;T;T;T;T;T;T;T;T

MetaSVM

Uncertain

-0.0087

MutationAssessor

Benign

0.90

L;.;.;.;.;.;L;.;.

PrimateAI

Pathogenic

0.93

PROVEAN

Benign

0.34

N;.;.;.;.;.;.;.;.

REVEL

Uncertain

0.47

Sift

Benign

0.050

D;.;.;.;.;.;.;.;.

Sift4G

Pathogenic

0.0010

D;D;D;D;D;D;D;D;D

Polyphen

0.90

P;.;.;.;.;.;P;.;.

Vest4

0.59

MVP

0.95

MPC

1.5

ClinPred

0.23

GERP RS

5.3

Varity_R

0.14

gMVP

0.73

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