rs1012018

Variant names:

• chr7-82232978-A-G
• rs1012018
• NM_000722.4:c.295-62369T>C

Your query was ambiguous. Multiple possible variants found:

• chr7-82232978-A-G
• chr7-82232978-A-T

Variant summary

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

The NM_000722.4(CACNA2D1):​c.295-62369T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.334 in 151,588 control chromosomes in the GnomAD database, including 10,068 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 0.33 (10068 hom., cov: 30)
• Consequence: CACNA2D1 NM_000722.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.12
• Publications: 2 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=-0.91).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.516 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA2D1	NM_000722.4	c.295-62369T>C		intron_variant	Intron 3 of 38	ENST00000356860.8	NP_000713.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA2D1	ENST00000356860.8	c.295-62369T>C		intron_variant	Intron 3 of 38	1	NM_000722.4	ENSP00000349320.3

Frequencies

GnomAD3 genomes AF: 0.334 AC: 50622 AN: 151472 Hom.: 10070 Cov.: 30

Gnomad AFR AF: 0.117

Gnomad AMI AF: 0.335

Gnomad AMR AF: 0.411

Gnomad ASJ AF: 0.293

Gnomad EAS AF: 0.533

Gnomad SAS AF: 0.394

Gnomad FIN AF: 0.533

Gnomad MID AF: 0.231

Gnomad NFE AF: 0.403

Gnomad OTH AF: 0.299

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

GnomAD4 genome AF: 0.334 AC: 50645 AN: 151588 Hom.: 10068 Cov.: 30 AF XY: 0.342 AC XY: 25333 AN XY: 74022

African (AFR) AF: 0.117 AC: 4827 AN: 41400

American (AMR) AF: 0.412 AC: 6249 AN: 15184

Ashkenazi Jewish (ASJ) AF: 0.293 AC: 1016 AN: 3468

East Asian (EAS) AF: 0.533 AC: 2735 AN: 5132

South Asian (SAS) AF: 0.394 AC: 1891 AN: 4800

European-Finnish (FIN) AF: 0.533 AC: 5538 AN: 10398

Middle Eastern (MID) AF: 0.224 AC: 66 AN: 294

European-Non Finnish (NFE) AF: 0.403 AC: 27384 AN: 67892

Other (OTH) AF: 0.300 AC: 634 AN: 2110

Alfa AF: 0.383 Hom.: 6096

Bravo AF: 0.314

Asia WGS AF: 0.437 AC: 1516 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	4.1
DANN	Benign	0.48
PhyloP100		1.1
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: rs1012018; hg19: chr7-81862294;