Genetic Variant CACNA2D1:c.355-5delT (chr7-82136680-CA-C) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP6_Very_StrongBS2

The NM_000722.4(CACNA2D1):c.355-5delT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00448 in 1,292,524 control chromosomes in the GnomAD database, including 1 homozygotes. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.00019 ( 0 hom., cov: 30)

Exomes 𝑓: 0.0050 ( 1 hom. )

Consequence

CACNA2D1
NM_000722.4 splice_region, intron

Scores

Not classified

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.0210

Variant links:

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 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -12 ACMG points.

BP6

Variant 7-82136680-CA-C is Benign according to our data. Variant chr7-82136680-CA-C is described in ClinVar as [Benign]. Clinvar id is 221019.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-82136680-CA-C is described in Lovd as [Benign]. Variant chr7-82136680-CA-C is described in Lovd as [Benign].

BS2

High AC in GnomAd4 at 27 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA2D1	NM_000722.4 link	c.355-5delT		splice_region_variant, intron_variant	Intron 4 of 38	ENST00000356860.8	NP_000713.2	P54289-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA2D1	ENST00000356860.8 link	c.355-5delT		splice_region_variant, intron_variant	Intron 4 of 38	1	NM_000722.4	ENSP00000349320.3		P54289-2

Frequencies

GnomAD3 genomes

AF:

0.000187

AC:

AN:

139182

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000131

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000727

Gnomad ASJ

AF:

0.000305

Gnomad EAS

AF:

0.000413

Gnomad SAS

AF:

0.000454

Gnomad FIN

AF:

0.000486

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000173

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0145

AC:

1693

AN:

116500

Hom.:

AF XY:

0.0153

AC XY:

953

AN XY:

62424

show subpopulations

Gnomad AFR exome

AF:

0.00746

Gnomad AMR exome

AF:

0.0134

Gnomad ASJ exome

AF:

0.0101

Gnomad EAS exome

AF:

0.0124

Gnomad SAS exome

AF:

0.0165

Gnomad FIN exome

AF:

0.0136

Gnomad NFE exome

AF:

0.0164

Gnomad OTH exome

AF:

0.0160

GnomAD4 exome

AF:

0.00499

AC:

5760

AN:

1153250

Hom.:

Cov.:

AF XY:

0.00498

AC XY:

2843

AN XY:

571038

show subpopulations

Gnomad4 AFR exome

AF:

0.00587

Gnomad4 AMR exome

AF:

0.00814

Gnomad4 ASJ exome

AF:

0.00298

Gnomad4 EAS exome

AF:

0.00182

Gnomad4 SAS exome

AF:

0.00650

Gnomad4 FIN exome

AF:

0.00546

Gnomad4 NFE exome

AF:

0.00494

Gnomad4 OTH exome

AF:

0.00418

GnomAD4 genome

AF:

0.000194

AC:

AN:

139274

Hom.:

Cov.:

AF XY:

0.000208

AC XY:

AN XY:

67300

show subpopulations

Gnomad4 AFR

AF:

0.000131

Gnomad4 AMR

AF:

0.000145

Gnomad4 ASJ

AF:

0.000305

Gnomad4 EAS

AF:

0.000414

Gnomad4 SAS

AF:

0.000456

Gnomad4 FIN

AF:

0.000486

Gnomad4 NFE

AF:

0.000173

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0159

Hom.:

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Brugada syndrome

Benign:1

Jan 15, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cardiovascular phenotype

Benign:1

Oct 21, 2019

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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

Below is the list of publications found by LitVar. It may be empty.

7-82136680-CAA-CA

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over