7-81969925-C-G

Position:

chr7-81969925-C-G

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_000722.4(CACNA2D1):c.2264G>C(p.Ser755Thr) variant causes a missense change. The variant allele was found at a frequency of 0.000635 in 1,608,622 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.00066 ( 1 hom., cov: 32)

Exomes 𝑓: 0.00063 ( 2 hom. )

Consequence

CACNA2D1
NM_000722.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 5.89

Variant links:

Genes affected

CACNA2D1 (HGNC:1399): (calcium voltage-gated channel auxiliary subunit alpha2delta 1) The preproprotein encoded by this gene is cleaved into multiple chains that comprise the alpha-2 and delta subunits of the voltage-dependent calcium channel complex. Calcium channels mediate the influx of calcium ions into the cell upon membrane polarization. Mutations in this gene can cause cardiac deficiencies, including Brugada syndrome and short QT syndrome. Alternate splicing results in multiple transcript variants, some of which may lack the delta subunit portion. [provided by RefSeq, Nov 2014]

CACNA2D1 links:

CACNA2D1 (HGNC:):

CACNA2D1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.011730015).

BP6

Variant 7-81969925-C-G is Benign according to our data. Variant chr7-81969925-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 180288.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-81969925-C-G is described in Lovd as [Likely_benign].

BS2

High AC in GnomAd4 at 100 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA2D1	NM_000722.4 linkuse as main transcript	c.2264G>C	p.Ser755Thr	missense_variant	28/39	ENST00000356860.8	NP_000713.2	P54289-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA2D1	ENST00000356860.8 linkuse as main transcript	c.2264G>C	p.Ser755Thr	missense_variant	28/39	1	NM_000722.4	ENSP00000349320.3		P54289-2

Frequencies

GnomAD3 genomes

AF:

0.000661

AC:

100

AN:

151300

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000968

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000265

Gnomad ASJ

AF:

0.0127

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000622

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000652

Gnomad OTH

AF:

0.000481

GnomAD3 exomes

AF:

0.000924

AC:

231

AN:

250028

Hom.:

AF XY:

0.000895

AC XY:

121

AN XY:

135162

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000756

Gnomad ASJ exome

AF:

0.0107

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000425

Gnomad FIN exome

AF:

0.0000464

Gnomad NFE exome

AF:

0.000691

Gnomad OTH exome

AF:

0.000987

GnomAD4 exome

AF:

0.000632

AC:

921

AN:

1457204

Hom.:

Cov.:

AF XY:

0.000662

AC XY:

480

AN XY:

725078

show subpopulations

Gnomad4 AFR exome

AF:

0.0000300

Gnomad4 AMR exome

AF:

0.000853

Gnomad4 ASJ exome

AF:

0.0101

Gnomad4 EAS exome

AF:

0.0000253

Gnomad4 SAS exome

AF:

0.000569

Gnomad4 FIN exome

AF:

0.0000188

Gnomad4 NFE exome

AF:

0.000457

Gnomad4 OTH exome

AF:

0.000948

GnomAD4 genome

AF:

0.000660

AC:

100

AN:

151418

Hom.:

Cov.:

AF XY:

0.000594

AC XY:

AN XY:

74048

show subpopulations

Gnomad4 AFR

AF:

0.0000965

Gnomad4 AMR

AF:

0.000264

Gnomad4 ASJ

AF:

0.0127

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000622

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000652

Gnomad4 OTH

AF:

0.000476

Alfa

AF:

0.00171

Hom.:

Bravo

AF:

0.000706

TwinsUK

AF:

0.00108

AC:

ALSPAC

AF:

0.00104

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00105

AC:

ExAC

AF:

0.000766

AC:

EpiCase

AF:

0.00148

EpiControl

AF:

0.000830

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 15, 2019	This variant is associated with the following publications: (PMID: 25527503, 21383000, 22840528, 29016797, 30847666) -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	CACNA2D1: BS2 -

Cardiac arrest

Benign:1

Likely benign, no assertion criteria provided

clinical testing

Blueprint Genetics

Dec 05, 2014

- -

Brugada syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 26, 2023

- -

Cardiovascular phenotype

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 10, 2017

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.33

BayesDel_addAF

Benign

-0.12

BayesDel_noAF

Uncertain

-0.030

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.13

.;T

Eigen

Uncertain

0.35

Eigen_PC

Uncertain

0.48

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.86

D;D

M_CAP

Benign

0.020

MetaRNN

Benign

0.012

T;T

MetaSVM

Benign

-0.41

MutationAssessor

Benign

1.8

.;L

PrimateAI

Uncertain

0.72

PROVEAN

Benign

-1.4

N;N

REVEL

Uncertain

0.33

Sift

Benign

0.092

T;T

Sift4G

Benign

0.088

T;T

Polyphen

0.43

B;.

Vest4

0.60

MVP

0.48

MPC

0.51

ClinPred

0.022

GERP RS

5.8

Varity_R

0.26

gMVP

0.92

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