7-81974525-C-T

Variant names:

• chr7-81974525-C-T
• rs75158917
• NM_000722.4:c.1983G>A

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_000722.4(CACNA2D1):​c.1983G>A​(p.Ser661Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00232 in 1,564,042 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0019 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0024 (4 hom.)
• Consequence: CACNA2D1 NM_000722.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -1.23
• Publications: 4 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 -17 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.016).
• BP6: Variant 7-81974525-C-T is Benign according to our data. Variant chr7-81974525-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 238180.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.23 with no splicing effect.
• BS2: High Homozygotes in GnomAd4 at 3 AD,AR,Unknown gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA2D1	NM_000722.4	c.1983G>A	p.Ser661Ser	synonymous_variant	Exon 25 of 39	ENST00000356860.8	NP_000713.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA2D1	ENST00000356860.8	c.1983G>A	p.Ser661Ser	synonymous_variant	Exon 25 of 39	1	NM_000722.4	ENSP00000349320.3
CACNA2D1	ENST00000443883.2	c.2019G>A	p.Ser673Ser	synonymous_variant	Exon 25 of 39	5		ENSP00000409374.2
CACNA2D1	ENST00000705962.1	c.1863G>A	p.Ser621Ser	synonymous_variant	Exon 24 of 38			ENSP00000516190.1
CACNA2D1	ENST00000705961.1	c.1749G>A	p.Ser583Ser	synonymous_variant	Exon 23 of 37			ENSP00000516189.1

Frequencies

GnomAD3 genomes AF: 0.00191 AC: 289 AN: 150964 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.000780

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.000794

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000970

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00332

Gnomad OTH AF: 0.00145

GnomAD2 exomes AF: 0.00164 AC: 399 AN: 243696 AF XY: 0.00160

Gnomad AFR exome AF: 0.00109

Gnomad AMR exome AF: 0.000411

Gnomad ASJ exome AF: 0.00223

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00128

Gnomad NFE exome AF: 0.00281

Gnomad OTH exome AF: 0.00135

GnomAD4 exome AF: 0.00236 AC: 3339 AN: 1412968 Hom.: 4 Cov.: 25 AF XY: 0.00235 AC XY: 1657 AN XY: 705402

African (AFR) AF: 0.000986 AC: 32 AN: 32470

American (AMR) AF: 0.000473 AC: 21 AN: 44376

Ashkenazi Jewish (ASJ) AF: 0.00222 AC: 57 AN: 25652

East Asian (EAS) AF: 0.00 AC: 0 AN: 39138

South Asian (SAS) AF: 0.000200 AC: 17 AN: 84910

European-Finnish (FIN) AF: 0.00154 AC: 81 AN: 52690

Middle Eastern (MID) AF: 0.00286 AC: 16 AN: 5604

European-Non Finnish (NFE) AF: 0.00282 AC: 3012 AN: 1069486

Other (OTH) AF: 0.00176 AC: 103 AN: 58642

GnomAD4 genome AF: 0.00191 AC: 289 AN: 151074 Hom.: 3 Cov.: 32 AF XY: 0.00160 AC XY: 118 AN XY: 73716

African (AFR) AF: 0.000778 AC: 32 AN: 41144

American (AMR) AF: 0.000792 AC: 12 AN: 15142

Ashkenazi Jewish (ASJ) AF: 0.00144 AC: 5 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5154

South Asian (SAS) AF: 0.00 AC: 0 AN: 4752

European-Finnish (FIN) AF: 0.000970 AC: 10 AN: 10304

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00332 AC: 225 AN: 67820

Other (OTH) AF: 0.00143 AC: 3 AN: 2092

Alfa AF: 0.00386 Hom.: 3

Bravo AF: 0.00157

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

-

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Feb 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

CACNA2D1: BP4, BP7, BS2 -

Oct 05, 2017

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 07, 2021

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

-

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Brugada syndrome Benign:1

Jan 31, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cardiovascular phenotype Benign:1

Feb 09, 2016

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.71
CADD	Benign	5.6
DANN	Benign	0.54
PhyloP100		-1.2
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs75158917; hg19: chr7-81603841; COSMIC: COSV100666454; COSMIC: COSV100666454;