rs73151504

Variant names:

• chr7-82012184-G-A
• rs73151504
• NM_000722.4:c.1332C>T

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 0P and 15B. BP4_Moderate BP6_Very_Strong BP7 BS2

The NM_001366867.1(CACNA2D1):​c.1332C>T​(p.Val444Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0085 in 1,606,080 control chromosomes in the GnomAD database, including 92 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0068 (7 hom., cov: 32)
  • Exomes 𝑓: 0.0087 (85 hom.)
• Consequence: CACNA2D1 NM_001366867.1 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.450
• Publications: 5 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-AS1 (HGNC:40120): (CACNA2D1 antisense RNA 1)

ACMG classification

Our verdict: Benign. The variant received -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.43).
• BP6: Variant 7-82012184-G-A is Benign according to our data. Variant chr7-82012184-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 238179.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.45 with no splicing effect.
• BS2: High Homozygotes in GnomAd4 at 7 AD,AR,Unknown gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001366867.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CACNA2D1	NM_000722.4	MANE Select	c.1332C>T	p.Val444Val	synonymous	Exon 15 of 39	NP_000713.2
	CACNA2D1	NM_001366867.1		c.1332C>T	p.Val444Val	synonymous	Exon 15 of 39	NP_001353796.1
	CACNA2D1-AS1	NR_110076.1		n.86+2922G>A		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CACNA2D1	ENST00000356860.8	TSL:1 MANE Select	c.1332C>T	p.Val444Val	synonymous	Exon 15 of 39	ENSP00000349320.3
	CACNA2D1	ENST00000443883.2	TSL:5	c.1332C>T	p.Val444Val	synonymous	Exon 15 of 39	ENSP00000409374.2
	CACNA2D1	ENST00000957014.1		c.1332C>T	p.Val444Val	synonymous	Exon 15 of 39	ENSP00000627073.1

Frequencies

GnomAD3 genomes AF: 0.00675 AC: 1020 AN: 151056 Hom.: 7 Cov.: 32

Gnomad AFR AF: 0.00146

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00351

Gnomad ASJ AF: 0.00490

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00271

Gnomad FIN AF: 0.0158

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0104

Gnomad OTH AF: 0.00482

GnomAD2 exomes AF: 0.00785 AC: 1971 AN: 251110 AF XY: 0.00796

Gnomad AFR exome AF: 0.00105

Gnomad AMR exome AF: 0.00260

Gnomad ASJ exome AF: 0.00347

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.0183

Gnomad NFE exome AF: 0.0109

Gnomad OTH exome AF: 0.0103

GnomAD4 exome AF: 0.00868 AC: 12628 AN: 1454908 Hom.: 85 Cov.: 27 AF XY: 0.00861 AC XY: 6234 AN XY: 724274

African (AFR) AF: 0.00108 AC: 36 AN: 33286

American (AMR) AF: 0.00275 AC: 123 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.00353 AC: 92 AN: 26070

East Asian (EAS) AF: 0.0000505 AC: 2 AN: 39576

South Asian (SAS) AF: 0.00451 AC: 388 AN: 86116

European-Finnish (FIN) AF: 0.0201 AC: 1074 AN: 53308

Middle Eastern (MID) AF: 0.000696 AC: 4 AN: 5750

European-Non Finnish (NFE) AF: 0.00946 AC: 10460 AN: 1105936

Other (OTH) AF: 0.00746 AC: 449 AN: 60154

GnomAD4 genome AF: 0.00675 AC: 1021 AN: 151172 Hom.: 7 Cov.: 32 AF XY: 0.00653 AC XY: 482 AN XY: 73780

African (AFR) AF: 0.00146 AC: 60 AN: 41104

American (AMR) AF: 0.00351 AC: 53 AN: 15102

Ashkenazi Jewish (ASJ) AF: 0.00490 AC: 17 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5140

South Asian (SAS) AF: 0.00292 AC: 14 AN: 4794

European-Finnish (FIN) AF: 0.0158 AC: 164 AN: 10388

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.0104 AC: 703 AN: 67878

Other (OTH) AF: 0.00477 AC: 10 AN: 2096

Alfa AF: 0.0100 Hom.: 13

Bravo AF: 0.00530

Asia WGS AF: 0.00115 AC: 4 AN: 3476

EpiCase AF: 0.00895

EpiControl AF: 0.00788

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	2	not provided (2)
-	-	1	Brugada syndrome (1)
-	-	1	Cardiovascular phenotype (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.43
CADD	Benign	3.4
DANN	Benign	0.72
PhyloP100		-0.45
Mutation Taster		=87/13	polymorphism

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

Other links and lift over

dbSNP: rs73151504; hg19: chr7-81641500; COSMIC: COSV100667870;