chrX-111251613-C-G

Variant names:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_014289.4(CAPN6):c.829G>C(p.Val277Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0591 in 1,207,785 control chromosomes in the GnomAD database, including 9,167 homozygotes. There are 20,632 hemizygotes in GnomAD. 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 Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

Frequency

Genomes: 𝑓 0.20 ( 4485 hom., 5876 hem., cov: 22)

Exomes 𝑓: 0.045 ( 4682 hom. 14756 hem. )

Consequence

CAPN6
NM_014289.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 2.52

Variant links:

Genes affected

CAPN6 (HGNC:1483): (calpain 6) Calpains are ubiquitous, well-conserved family of calcium-dependent, cysteine proteases. The calpain proteins are heterodimers consisting of an invariant small subunit and variable large subunits. The large subunit possesses a cysteine protease domain, and both subunits possess calcium-binding domains. Calpains have been implicated in neurodegenerative processes, as their activation can be triggered by calcium influx and oxidative stress. The protein encoded by this gene is highly expressed in the placenta. Its C-terminal region lacks any homology to the calmodulin-like domain of other calpains. The protein lacks critical active site residues and thus is suggested to be proteolytically inactive. The protein may play a role in tumor formation by inhibiting apoptosis and promoting angiogenesis. [provided by RefSeq, Nov 2009]

CAPN6 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=1.9559777E-5).

BP6

Variant X-111251613-C-G is Benign according to our data. Variant chrX-111251613-C-G is described in ClinVar as [Benign]. Clinvar id is 1288617.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.611 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CAPN6	NM_014289.4 link	c.829G>C	p.Val277Leu	missense_variant	Exon 6 of 13	ENST00000324068.2	NP_055104.2	Q9Y6Q1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CAPN6	ENST00000324068.2 link	c.829G>C	p.Val277Leu	missense_variant	Exon 6 of 13	1	NM_014289.4	ENSP00000317214.1		Q9Y6Q1

Frequencies

GnomAD3 genomes

AF:

0.196

AC:

21791

AN:

111161

Hom.:

4480

Cov.:

AF XY:

0.175

AC XY:

5832

AN XY:

33387

show subpopulations

Gnomad AFR

AF:

0.618

Gnomad AMI

AF:

0.00581

Gnomad AMR

AF:

0.0983

Gnomad ASJ

AF:

0.0194

Gnomad EAS

AF:

0.00140

Gnomad SAS

AF:

0.0110

Gnomad FIN

AF:

0.0123

Gnomad MID

AF:

0.125

Gnomad NFE

AF:

0.0310

Gnomad OTH

AF:

0.169

GnomAD3 exomes

AF:

0.0715

AC:

13119

AN:

183409

Hom.:

2096

AF XY:

0.0542

AC XY:

3677

AN XY:

67861

show subpopulations

Gnomad AFR exome

AF:

0.630

Gnomad AMR exome

AF:

0.0525

Gnomad ASJ exome

AF:

0.0248

Gnomad EAS exome

AF:

0.000721

Gnomad SAS exome

AF:

0.00917

Gnomad FIN exome

AF:

0.0151

Gnomad NFE exome

AF:

0.0306

Gnomad OTH exome

AF:

0.0594

GnomAD4 exome

AF:

0.0452

AC:

49518

AN:

1096571

Hom.:

4682

Cov.:

AF XY:

0.0408

AC XY:

14756

AN XY:

362007

show subpopulations

Gnomad4 AFR exome

AF:

0.638

Gnomad4 AMR exome

AF:

0.0594

Gnomad4 ASJ exome

AF:

0.0232

Gnomad4 EAS exome

AF:

0.000497

Gnomad4 SAS exome

AF:

0.0108

Gnomad4 FIN exome

AF:

0.0151

Gnomad4 NFE exome

AF:

0.0299

Gnomad4 OTH exome

AF:

0.0738

GnomAD4 genome

AF:

0.196

AC:

21843

AN:

111214

Hom.:

4485

Cov.:

AF XY:

0.176

AC XY:

5876

AN XY:

33450

show subpopulations

Gnomad4 AFR

AF:

0.618

Gnomad4 AMR

AF:

0.0981

Gnomad4 ASJ

AF:

0.0194

Gnomad4 EAS

AF:

0.00141

Gnomad4 SAS

AF:

0.0102

Gnomad4 FIN

AF:

0.0123

Gnomad4 NFE

AF:

0.0310

Gnomad4 OTH

AF:

0.166

Alfa

AF:

0.0565

Hom.:

1620

Bravo

AF:

0.225

TwinsUK

AF:

0.0286

AC:

106

ALSPAC

AF:

0.0294

AC:

ESP6500AA

AF:

0.611

AC:

2345

ESP6500EA

AF:

0.0314

AC:

211

ExAC

AF:

0.0772

AC:

9379

EpiCase

AF:

0.0317

EpiControl

AF:

0.0327

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 09, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.86

BayesDel_noAF

Benign

-0.86

CADD

Benign

DANN

Benign

0.51

DEOGEN2

Benign

0.038

FATHMM_MKL

Benign

0.32

LIST_S2

Benign

0.10

MetaRNN

Benign

0.000020

MetaSVM

Benign

-0.94

MutationAssessor

Benign

-0.78

PrimateAI

Uncertain

0.54

PROVEAN

Benign

1.1

REVEL

Benign

0.069

Sift

Benign

1.0

Sift4G

Benign

1.0

Polyphen

0.0

Vest4

0.010

MutPred

0.24

Loss of MoRF binding (P = 0.1034);

MPC

0.44

ClinPred

0.0045

GERP RS

5.3

Varity_R

0.068

gMVP

0.40

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