rs75158917

Positions:

• chr7-81974525-C-T

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_000722.4(CACNA2D1):​c.1983G>A​(p.Ser661=) 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

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 -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.71).
• 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. Variant chr7-81974525-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-1.23 with no splicing effect.
• BS2: High AC in GnomAd4 at 289 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CACNA2D1	NM_000722.4	c.1983G>A	p.Ser661=	synonymous_variant	25/39	ENST00000356860.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CACNA2D1	ENST00000356860.8	c.1983G>A	p.Ser661=	synonymous_variant	25/39	1	NM_000722.4
CACNA2D1	ENST00000443883.2	c.2019G>A	p.Ser673=	synonymous_variant	25/39	5		P1
CACNA2D1	ENST00000705962.1	c.1863G>A	p.Ser621=	synonymous_variant	24/38
CACNA2D1	ENST00000705961.1	c.1752G>A	p.Ser584=	synonymous_variant	23/37

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

GnomAD3 exomes AF: 0.00164 AC: 399 AN: 243696 Hom.: 0 AF XY: 0.00160 AC XY: 211 AN XY: 131788

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 SAS exome AF: 0.000167

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

Gnomad4 AFR exome AF: 0.000986

Gnomad4 AMR exome AF: 0.000473

Gnomad4 ASJ exome AF: 0.00222

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000200

Gnomad4 FIN exome AF: 0.00154

Gnomad4 NFE exome AF: 0.00282

Gnomad4 OTH exome AF: 0.00176

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

Gnomad4 AFR AF: 0.000778

Gnomad4 AMR AF: 0.000792

Gnomad4 ASJ AF: 0.00144

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000970

Gnomad4 NFE AF: 0.00332

Gnomad4 OTH AF: 0.00143

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

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	CACNA2D1: BP4, BP7, BS2 -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 07, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Oct 05, 2017	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

not specified Benign:1

Benign, no assertion criteria provided

clinical testing

Clinical Genetics, Academic Medical Center

-

- -

Brugada syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Cardiovascular phenotype Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 09, 2016

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

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

Publications

LitVar

Other links and lift over

dbSNP: rs75158917; hg19: chr7-81603841; COSMIC: COSV100666454; COSMIC: COSV100666454;