rs1229502

Positions:

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BA1

The NM_000722.4(CACNA2D1):c.3114C>T(p.Pro1038=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.295 in 1,606,426 control chromosomes in the GnomAD database, including 72,019 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.25 ( 5505 hom., cov: 32)

Exomes 𝑓: 0.30 ( 66514 hom. )

Consequence

CACNA2D1
NM_000722.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 0.215

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.4).

BP6

Variant 7-81959320-G-A is Benign according to our data. Variant chr7-81959320-G-A is described in ClinVar as [Benign]. Clinvar id is 256767.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-81959320-G-A is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=0.215 with no splicing effect.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.306 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA2D1	NM_000722.4 linkuse as main transcript	c.3114C>T	p.Pro1038=	synonymous_variant	38/39	ENST00000356860.8	NP_000713.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA2D1	ENST00000356860.8 linkuse as main transcript	c.3114C>T	p.Pro1038=	synonymous_variant	38/39	1	NM_000722.4	ENSP00000349320		P54289-2
CACNA2D1	ENST00000443883.2 linkuse as main transcript	c.3150C>T	p.Pro1050=	synonymous_variant	38/39	5		ENSP00000409374	P1	P54289-1
CACNA2D1	ENST00000705962.1 linkuse as main transcript	c.2994C>T	p.Pro998=	synonymous_variant	37/38			ENSP00000516190
CACNA2D1	ENST00000705961.1 linkuse as main transcript	c.2883C>T	p.Pro961=	synonymous_variant	36/37			ENSP00000516189

Frequencies

GnomAD3 genomes

AF:

0.255

AC:

38638

AN:

151658

Hom.:

5504

Cov.:

show subpopulations

Gnomad AFR

AF:

0.136

Gnomad AMI

AF:

0.114

Gnomad AMR

AF:

0.302

Gnomad ASJ

AF:

0.318

Gnomad EAS

AF:

0.234

Gnomad SAS

AF:

0.276

Gnomad FIN

AF:

0.287

Gnomad MID

AF:

0.277

Gnomad NFE

AF:

0.310

Gnomad OTH

AF:

0.277

GnomAD3 exomes

AF:

0.291

AC:

72862

AN:

250768

Hom.:

11027

AF XY:

0.292

AC XY:

39629

AN XY:

135524

show subpopulations

Gnomad AFR exome

AF:

0.133

Gnomad AMR exome

AF:

0.342

Gnomad ASJ exome

AF:

0.318

Gnomad EAS exome

AF:

0.237

Gnomad SAS exome

AF:

0.286

Gnomad FIN exome

AF:

0.285

Gnomad NFE exome

AF:

0.306

Gnomad OTH exome

AF:

0.290

GnomAD4 exome

AF:

0.299

AC:

435612

AN:

1454650

Hom.:

66514

Cov.:

AF XY:

0.300

AC XY:

217288

AN XY:

724108

show subpopulations

Gnomad4 AFR exome

AF:

0.128

Gnomad4 AMR exome

AF:

0.336

Gnomad4 ASJ exome

AF:

0.319

Gnomad4 EAS exome

AF:

0.281

Gnomad4 SAS exome

AF:

0.290

Gnomad4 FIN exome

AF:

0.290

Gnomad4 NFE exome

AF:

0.305

Gnomad4 OTH exome

AF:

0.290

GnomAD4 genome

AF:

0.255

AC:

38636

AN:

151776

Hom.:

5505

Cov.:

AF XY:

0.256

AC XY:

18954

AN XY:

74154

show subpopulations

Gnomad4 AFR

AF:

0.136

Gnomad4 AMR

AF:

0.302

Gnomad4 ASJ

AF:

0.318

Gnomad4 EAS

AF:

0.234

Gnomad4 SAS

AF:

0.276

Gnomad4 FIN

AF:

0.287

Gnomad4 NFE

AF:

0.310

Gnomad4 OTH

AF:

0.273

Alfa

AF:

0.301

Hom.:

5142

Bravo

AF:

0.250

Asia WGS

AF:

0.215

AC:

748

AN:

3478

EpiCase

AF:

0.310

EpiControl

AF:

0.312

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 28, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided

Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Apr 20, 2017	- -

Brugada syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Cardiovascular phenotype

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 19, 2015

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

BayesDel_noAF

Benign

-0.40

CADD

Benign

DANN

Benign

0.62

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