7-82156904-C-T

Variant names:

• chr7-82156904-C-T
• rs2367911
• NM_000722.4:c.354+13646G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000722.4(CACNA2D1):​c.354+13646G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.11 in 151,954 control chromosomes in the GnomAD database, including 1,571 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.11 (1571 hom., cov: 33)
• Consequence: CACNA2D1 NM_000722.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.379
• 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 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.54).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.24 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA2D1	NM_000722.4	c.354+13646G>A		intron_variant	Intron 4 of 38	ENST00000356860.8	NP_000713.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA2D1	ENST00000356860.8	c.354+13646G>A		intron_variant	Intron 4 of 38	1	NM_000722.4	ENSP00000349320.3

Frequencies

GnomAD3 genomes AF: 0.110 AC: 16709 AN: 151836 Hom.: 1566 Cov.: 33

Gnomad AFR AF: 0.244

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.123

Gnomad ASJ AF: 0.105

Gnomad EAS AF: 0.158

Gnomad SAS AF: 0.133

Gnomad FIN AF: 0.0505

Gnomad MID AF: 0.168

Gnomad NFE AF: 0.0311

Gnomad OTH AF: 0.113

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.110 AC: 16744 AN: 151954 Hom.: 1571 Cov.: 33 AF XY: 0.112 AC XY: 8289 AN XY: 74286

African (AFR) AF: 0.244 AC: 10100 AN: 41414

American (AMR) AF: 0.122 AC: 1866 AN: 15248

Ashkenazi Jewish (ASJ) AF: 0.105 AC: 365 AN: 3464

East Asian (EAS) AF: 0.158 AC: 815 AN: 5154

South Asian (SAS) AF: 0.133 AC: 640 AN: 4820

European-Finnish (FIN) AF: 0.0505 AC: 534 AN: 10580

Middle Eastern (MID) AF: 0.173 AC: 51 AN: 294

European-Non Finnish (NFE) AF: 0.0312 AC: 2117 AN: 67956

Other (OTH) AF: 0.120 AC: 254 AN: 2112

Alfa AF: 0.0843 Hom.: 350

Bravo AF: 0.121

Asia WGS AF: 0.169 AC: 588 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.54
CADD	Benign	12
DANN	Benign	0.71
PhyloP100		0.38
Mutation Taster		=100/0	polymorphism (auto)

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: rs2367911; hg19: chr7-81786220;