NM_000722.4:c.2126G>A

Variant names:

• chr7-81971792-C-T
• rs78086631
• NM_000722.4:c.2126G>A

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_000722.4(CACNA2D1):​c.2126G>A​(p.Ser709Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00332 in 1,588,146 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0023 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0034 (13 hom.)
• Consequence: CACNA2D1 NM_000722.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 2.56
• Publications: 20 publications found

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 Gene-Disease associations (from GenCC):

• short QT syndrome

  Inheritance: AD Classification: SUPPORTIVE, NO_KNOWN Submitted by: ClinGen, Orphanet
• Brugada syndrome

  Inheritance: AD, Unknown Classification: LIMITED, NO_KNOWN Submitted by: Ambry Genetics, Genomics England PanelApp
• genetic developmental and epileptic encephalopathy

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
• developmental and epileptic encephalopathy 110

  Inheritance: AR Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae), G2P
• Brugada syndrome 1

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008761466).
• BP6: Variant 7-81971792-C-T is Benign according to our data. Variant chr7-81971792-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 416572.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAdExome4 at 13 AD,AR,Unknown gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000722.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CACNA2D1	NM_000722.4	MANE Select	c.2126G>A	p.Ser709Asn	missense	Exon 26 of 39	NP_000713.2
	CACNA2D1	NM_001366867.1		c.2162G>A	p.Ser721Asn	missense	Exon 26 of 39	NP_001353796.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CACNA2D1	ENST00000356860.8	TSL:1 MANE Select	c.2126G>A	p.Ser709Asn	missense	Exon 26 of 39	ENSP00000349320.3
	CACNA2D1	ENST00000443883.2	TSL:5	c.2162G>A	p.Ser721Asn	missense	Exon 26 of 39	ENSP00000409374.2
	CACNA2D1	ENST00000705962.1		c.2006G>A	p.Ser669Asn	missense	Exon 25 of 38	ENSP00000516190.1

Frequencies

GnomAD3 genomes AF: 0.00227 AC: 344 AN: 151696 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000580

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000989

Gnomad ASJ AF: 0.00260

Gnomad EAS AF: 0.000386

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.00217

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00384

Gnomad OTH AF: 0.00240

GnomAD2 exomes AF: 0.00254 AC: 636 AN: 250464 AF XY: 0.00269

Gnomad AFR exome AF: 0.000495

Gnomad AMR exome AF: 0.00110

Gnomad ASJ exome AF: 0.00379

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00342

Gnomad NFE exome AF: 0.00391

Gnomad OTH exome AF: 0.00361

GnomAD4 exome AF: 0.00343 AC: 4926 AN: 1436332 Hom.: 13 Cov.: 27 AF XY: 0.00348 AC XY: 2490 AN XY: 716062

African (AFR) AF: 0.000577 AC: 19 AN: 32918

American (AMR) AF: 0.00121 AC: 54 AN: 44614

Ashkenazi Jewish (ASJ) AF: 0.00383 AC: 99 AN: 25846

East Asian (EAS) AF: 0.00 AC: 0 AN: 39396

South Asian (SAS) AF: 0.000550 AC: 47 AN: 85486

European-Finnish (FIN) AF: 0.00337 AC: 180 AN: 53358

Middle Eastern (MID) AF: 0.000175 AC: 1 AN: 5700

European-Non Finnish (NFE) AF: 0.00398 AC: 4334 AN: 1089540

Other (OTH) AF: 0.00323 AC: 192 AN: 59474

GnomAD4 genome AF: 0.00227 AC: 344 AN: 151814 Hom.: 0 Cov.: 32 AF XY: 0.00202 AC XY: 150 AN XY: 74212

African (AFR) AF: 0.000579 AC: 24 AN: 41486

American (AMR) AF: 0.000987 AC: 15 AN: 15192

Ashkenazi Jewish (ASJ) AF: 0.00260 AC: 9 AN: 3466

East Asian (EAS) AF: 0.000387 AC: 2 AN: 5172

South Asian (SAS) AF: 0.00124 AC: 6 AN: 4824

European-Finnish (FIN) AF: 0.00217 AC: 23 AN: 10602

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00384 AC: 260 AN: 67760

Other (OTH) AF: 0.00237 AC: 5 AN: 2108

Alfa AF: 0.00365 Hom.: 1

Bravo AF: 0.00238

TwinsUK AF: 0.00351 AC: 13

ALSPAC AF: 0.00311 AC: 12

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00547 AC: 47

ExAC AF: 0.00268 AC: 325

Asia WGS AF: 0.000289 AC: 1 AN: 3468

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Apr 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

CACNA2D1: PP2, BS1, BS2

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Mar 03, 2022

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 23874304, 30027834, 27711072, 25527503, 23414114, 20817017, 26498160, 22840528, 26707467, 30821013)

not specified Benign:2

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Brugada syndrome Benign:1

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Cardiovascular phenotype Benign:1

Nov 10, 2021

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely 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.

CACNA2D1-related disorder Benign:1

Mar 27, 2019

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	22
DANN	Benign	0.97
DEOGEN2	Benign	0.041	T
Eigen	Benign	0.17
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.80	T
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.0088	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.34	N
PhyloP100		2.6
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	0.86	N
REVEL	Benign	0.10
Sift	Benign	0.26	T
Sift4G	Benign	1.0	T
Polyphen		0.0030	B
Vest4		0.15
MVP		0.11
MPC		0.43
ClinPred		0.011	T
GERP RS		5.2
Varity_R		0.094
gMVP		0.58
Mutation Taster		=96/4	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
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

Other links and lift over

dbSNP: rs78086631; hg19: chr7-81601108; COSMIC: COSV62391757; COSMIC: COSV62391757;