rs37133

Positions:

• chr7-82012237-A-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000722.4(CACNA2D1):​c.1279T>C​(p.Leu427Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00412 in 1,578,384 control chromosomes in the GnomAD database, including 217 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.021 (99 hom., cov: 32)
  • Exomes 𝑓: 0.0024 (118 hom.)
• Consequence: CACNA2D1 NM_000722.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 2.75

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.48).
• BP6: Variant 7-82012237-A-G is Benign according to our data. Variant chr7-82012237-A-G is described in ClinVar as [Benign]. Clinvar id is 381781.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-82012237-A-G is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=2.75 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0693 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA2D1	NM_000722.4	c.1279T>C	p.Leu427Leu	synonymous_variant	15/39	ENST00000356860.8	NP_000713.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA2D1	ENST00000356860.8	c.1279T>C	p.Leu427Leu	synonymous_variant	15/39	1	NM_000722.4	ENSP00000349320.3

Frequencies

GnomAD3 genomes AF: 0.0206 AC: 3053 AN: 148268 Hom.: 99 Cov.: 32

Gnomad AFR AF: 0.0716

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00933

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000198

Gnomad SAS AF: 0.000638

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0136

Gnomad NFE AF: 0.000593

Gnomad OTH AF: 0.0178

GnomAD3 exomes AF: 0.00587 AC: 1466 AN: 249652 Hom.: 61 AF XY: 0.00453 AC XY: 611 AN XY: 134900

Gnomad AFR exome AF: 0.0718

Gnomad AMR exome AF: 0.00511

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00118

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000638

Gnomad OTH exome AF: 0.00279

GnomAD4 exome AF: 0.00241 AC: 3442 AN: 1430004 Hom.: 118 Cov.: 25 AF XY: 0.00212 AC XY: 1511 AN XY: 713242

Gnomad4 AFR exome AF: 0.0716

Gnomad4 AMR exome AF: 0.00569

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000507

Gnomad4 SAS exome AF: 0.000912

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000394

Gnomad4 OTH exome AF: 0.00522

GnomAD4 genome AF: 0.0206 AC: 3060 AN: 148380 Hom.: 99 Cov.: 32 AF XY: 0.0203 AC XY: 1466 AN XY: 72330

Gnomad4 AFR AF: 0.0715

Gnomad4 AMR AF: 0.00932

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000199

Gnomad4 SAS AF: 0.000639

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000593

Gnomad4 OTH AF: 0.0176

Alfa AF: 0.00638 Hom.: 34

Bravo AF: 0.0231

Asia WGS AF: 0.0100 AC: 35 AN: 3476

EpiCase AF: 0.000600

EpiControl AF: 0.00125

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 05, 2016	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. -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	May 03, 2017	- -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Brugada syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 16, 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
BayesDel_noAF	Benign	-0.48
CADD	Benign	9.6
DANN	Benign	0.91

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: rs37133; hg19: chr7-81641553;