Variant 7-81950430-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_000722.4(CACNA2D1):c.3238C>T(p.Leu1080Phe) variant causes a missense change. The variant allele was found at a frequency of 0.00000753 in 1,461,210 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000075 ( 0 hom. )

Consequence

CACNA2D1
NM_000722.4 missense

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: 5.61

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:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.291632).

BS2

High AC in GnomAdExome4 at 11 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA2D1	NM_000722.4 linkuse as main transcript	c.3238C>T	p.Leu1080Phe	missense_variant	39/39	ENST00000356860.8	NP_000713.2	P54289-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
CACNA2D1	ENST00000356860.8 linkuse as main transcript	c.3238C>T	p.Leu1080Phe	missense_variant	39/39	1	NM_000722.4	ENSP00000349320.3	P54289-2
CACNA2D1	ENST00000443883.2 linkuse as main transcript	c.3274C>T	p.Leu1092Phe	missense_variant	39/39	5		ENSP00000409374.2	P54289-1H0Y715
CACNA2D1	ENST00000705962.1 linkuse as main transcript	c.3118C>T	p.Leu1040Phe	missense_variant	38/38			ENSP00000516190.1	A0A994J595
CACNA2D1	ENST00000705961.1 linkuse as main transcript	c.3004C>T	p.Leu1002Phe	missense_variant	37/37			ENSP00000516189.1	A0A994J5M8

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000239

AC:

AN:

250874

Hom.:

AF XY:

0.0000148

AC XY:

AN XY:

135578

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:

0.000196

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000753

AC:

AN:

1461210

Hom.:

Cov.:

AF XY:

0.00000963

AC XY:

AN XY:

726910

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:

0.000128

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000247

AC:

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Cardiovascular phenotype

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 04, 2024

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

0.083

BayesDel_addAF

Benign

-0.24

BayesDel_noAF

Benign

-0.31

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.25

.;T

Eigen

Uncertain

0.34

Eigen_PC

Uncertain

0.42

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Benign

0.84

T;T

M_CAP

Benign

0.021

MetaRNN

Benign

0.29

T;T

MetaSVM

Benign

-0.83

MutationAssessor

Uncertain

2.2

.;M

PrimateAI

Benign

0.48

PROVEAN

Benign

-1.9

N;N

REVEL

Benign

0.14

Sift

Uncertain

0.0070

D;D

Sift4G

Uncertain

0.056

T;T

Polyphen

0.063

B;.

Vest4

0.47

MVP

0.18

MPC

0.58

ClinPred

0.35

GERP RS

5.0

Varity_R

0.35

gMVP

0.68

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