Variant 11-65182901-G-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_005186.4(CAPN1):c.200G>T(p.Ser67Ile) variant causes a missense change. The variant allele was found at a frequency of 0.0000255 in 1,609,198 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000023 ( 0 hom. )

Consequence

CAPN1
NM_005186.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.66

Variant links:

Genes affected

CAPN1 (HGNC:1476): (calpain 1) The calpains, calcium-activated neutral proteases, are nonlysosomal, intracellular cysteine proteases. The mammalian calpains include ubiquitous, stomach-specific, and muscle-specific proteins. The ubiquitous enzymes consist of heterodimers with distinct large, catalytic subunits associated with a common small, regulatory subunit. This gene encodes the large subunit of the ubiquitous enzyme, calpain 1. Several transcript variants encoding two different isoforms have been found for this gene. [provided by RefSeq, Nov 2010]

CAPN1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.79

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CAPN1	NM_005186.4 linkuse as main transcript	c.200G>T	p.Ser67Ile	missense_variant	2/22	ENST00000279247.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CAPN1	ENST00000279247.11 linkuse as main transcript	c.200G>T	p.Ser67Ile	missense_variant	2/22	1	NM_005186.4	P1

Frequencies

GnomAD3 genomes

AF:

0.0000460

AC:

AN:

152182

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:

0.000565

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000376

AC:

AN:

239570

Hom.:

AF XY:

0.0000461

AC XY:

AN XY:

130030

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000427

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000233

AC:

AN:

1457016

Hom.:

Cov.:

AF XY:

0.0000262

AC XY:

AN XY:

724382

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:

0.000527

Gnomad4 NFE exome

AF:

0.00000451

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000460

AC:

AN:

152182

Hom.:

Cov.:

AF XY:

0.0000672

AC XY:

AN XY:

74350

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:

0.000565

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000317

Hom.:

Bravo

AF:

0.00000756

ExAC

AF:

0.0000414

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 05, 2023

The c.200G>T (p.S67I) alteration is located in exon 2 (coding exon 1) of the CAPN1 gene. This alteration results from a G to T substitution at nucleotide position 200, causing the serine (S) at amino acid position 67 to be replaced by an isoleucine (I). 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

0.49

BayesDel_addAF

Pathogenic

0.20

BayesDel_noAF

Uncertain

0.040

Cadd

Pathogenic

Dann

Uncertain

0.98

DEOGEN2

Uncertain

0.66

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

Eigen

Pathogenic

0.77

Eigen_PC

Uncertain

0.61

FATHMM_MKL

Uncertain

0.78

LIST_S2

Benign

0.79

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

M_CAP

Uncertain

0.22

MetaRNN

Pathogenic

0.79

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

MetaSVM

Pathogenic

0.83

MutationTaster

Benign

1.0

D;D;D;D;D

PrimateAI

Uncertain

0.61

PROVEAN

Uncertain

-4.2

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

REVEL

Uncertain

0.64

Sift

Uncertain

0.0070

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

Sift4G

Uncertain

0.016

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

Polyphen

0.99

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

Vest4

0.66, 0.66, 0.58

MutPred

0.81

Loss of disorder (P = 0.0122);Loss of disorder (P = 0.0122);Loss of disorder (P = 0.0122);Loss of disorder (P = 0.0122);Loss of disorder (P = 0.0122);Loss of disorder (P = 0.0122);Loss of disorder (P = 0.0122);Loss of disorder (P = 0.0122);Loss of disorder (P = 0.0122);Loss of disorder (P = 0.0122);Loss of disorder (P = 0.0122);Loss of disorder (P = 0.0122);Loss of disorder (P = 0.0122);

MVP

0.97

MPC

1.1

ClinPred

0.94

GERP RS

3.0

Varity_R

0.75

gMVP

0.94

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.070

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