rs35131433

chr7-81959300-T-G

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_000722.4(CACNA2D1):c.3134A>C(p.Asp1045Ala) variant causes a missense change. The variant allele was found at a frequency of 0.0052 in 1,610,030 control chromosomes in the GnomAD database, including 38 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0036 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0054 (36 hom.)
• Consequence: CACNA2D1 NM_000722.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 5.63

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]

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.009257674).
• BP6: Variant 7-81959300-T-G is Benign according to our data. Variant chr7-81959300-T-G is described in ClinVar as [Likely_benign]. Clinvar id is 263797.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-81959300-T-G is described in Lovd as [Benign].
• BS2: High AC in GnomAd at 550 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CACNA2D1	NM_000722.4	c.3134A>C	p.Asp1045Ala	missense_variant	38/39	ENST00000356860.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CACNA2D1	ENST00000356860.8	c.3134A>C	p.Asp1045Ala	missense_variant	38/39	1	NM_000722.4
CACNA2D1	ENST00000443883.2	c.3170A>C	p.Asp1057Ala	missense_variant	38/39	5		P1
CACNA2D1	ENST00000705962.1	c.3014A>C	p.Asp1005Ala	missense_variant	37/38
CACNA2D1	ENST00000705961.1	c.2903A>C	p.Asp968Ala	missense_variant	36/37

Frequencies

GnomAD3 genomes AF: 0.00362 AC: 550 AN: 152052 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.00123

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00118

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00151

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00680

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.00299 AC: 749 AN: 250800 Hom.: 1 AF XY: 0.00306 AC XY: 415 AN XY: 135554

Gnomad AFR exome AF: 0.00117

Gnomad AMR exome AF: 0.000869

Gnomad ASJ exome AF: 0.000497

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000523

Gnomad FIN exome AF: 0.00162

Gnomad NFE exome AF: 0.00550

Gnomad OTH exome AF: 0.00344

GnomAD4 exome AF: 0.00536 AC: 7821 AN: 1457860 Hom.: 36 Cov.: 28 AF XY: 0.00521 AC XY: 3778 AN XY: 725500

Gnomad4 AFR exome AF: 0.00102

Gnomad4 AMR exome AF: 0.000784

Gnomad4 ASJ exome AF: 0.000307

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000429

Gnomad4 FIN exome AF: 0.00137

Gnomad4 NFE exome AF: 0.00670

Gnomad4 OTH exome AF: 0.00339

GnomAD4 genome AF: 0.00361 AC: 550 AN: 152170 Hom.: 2 Cov.: 32 AF XY: 0.00323 AC XY: 240 AN XY: 74382

Gnomad4 AFR AF: 0.00123

Gnomad4 AMR AF: 0.00118

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00151

Gnomad4 NFE AF: 0.00680

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.00560 Hom.: 7

Bravo AF: 0.00339

TwinsUK AF: 0.00620 AC: 23

ALSPAC AF: 0.00727 AC: 28

ESP6500AA AF: 0.00250 AC: 11

ESP6500EA AF: 0.00640 AC: 55

ExAC AF: 0.00279 AC: 339

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00568

EpiControl AF: 0.00510

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 05, 2017	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. -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

-

- -

Brugada syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 09, 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
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Uncertain	-0.070
Cadd	Benign	23
Dann	Uncertain	0.99
Eigen	Uncertain	0.21
Eigen_PC	Uncertain	0.35
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.73	T;T
M_CAP	Benign	0.027	D
MetaRNN	Benign	0.0093	T;T
MetaSVM	Benign	-0.78	T
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.55	T
PROVEAN	Uncertain	-2.6	D;D
REVEL	Benign	0.25
Sift	Benign	0.11	T;T
Sift4G	Benign	0.18	T;T
Polyphen		0.030	B;.
Vest4		0.39
MVP		0.20
MPC		0.59
ClinPred		0.026	T
GERP RS		5.8
Varity_R		0.33
gMVP		0.84

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

Other links and lift over

dbSNP: rs35131433; hg19: chr7-81588616; COSMIC: COSV99070867; COSMIC: COSV99070867;