chr7-81963904-T-C

Variant names:

• chr7-81963904-T-C
• rs1029847
• NM_000722.4:c.2780+152A>G

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_000722.4(CACNA2D1):​c.2780+152A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.218 in 669,750 control chromosomes in the GnomAD database, including 16,559 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.23 (4146 hom., cov: 32)
  • Exomes 𝑓: 0.22 (12413 hom.)
• Consequence: CACNA2D1 NM_000722.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.0690
• Publications: 1 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: G2P, Labcorp Genetics (formerly Invitae)
• Brugada syndrome 1

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 7-81963904-T-C is Benign according to our data. Variant chr7-81963904-T-C is described in ClinVar as Benign. ClinVar VariationId is 1226323.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.274 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000722.4. 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.2780+152A>G		intron	N/A	NP_000713.2	P54289-2
	CACNA2D1	NM_001366867.1		c.2816+152A>G		intron	N/A	NP_001353796.1	P54289-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CACNA2D1	ENST00000356860.8	TSL:1 MANE Select	c.2780+152A>G		intron	N/A	ENSP00000349320.3	P54289-2
	CACNA2D1	ENST00000443883.2	TSL:5	c.2816+152A>G		intron	N/A	ENSP00000409374.2	H0Y715
	CACNA2D1	ENST00000957014.1		c.2801+152A>G		intron	N/A	ENSP00000627073.1

Frequencies

GnomAD3 genomes AF: 0.229 AC: 34763 AN: 151814 Hom.: 4139 Cov.: 32

Gnomad AFR AF: 0.278

Gnomad AMI AF: 0.175

Gnomad AMR AF: 0.216

Gnomad ASJ AF: 0.195

Gnomad EAS AF: 0.194

Gnomad SAS AF: 0.238

Gnomad FIN AF: 0.205

Gnomad MID AF: 0.272

Gnomad NFE AF: 0.209

Gnomad OTH AF: 0.243

GnomAD4 exome AF: 0.215 AC: 111498 AN: 517818 Hom.: 12413 AF XY: 0.214 AC XY: 59355 AN XY: 277172

African (AFR) AF: 0.285 AC: 3811 AN: 13376

American (AMR) AF: 0.204 AC: 4970 AN: 24394

Ashkenazi Jewish (ASJ) AF: 0.189 AC: 3002 AN: 15876

East Asian (EAS) AF: 0.241 AC: 7540 AN: 31282

South Asian (SAS) AF: 0.216 AC: 10901 AN: 50470

European-Finnish (FIN) AF: 0.200 AC: 8818 AN: 44084

Middle Eastern (MID) AF: 0.223 AC: 467 AN: 2092

European-Non Finnish (NFE) AF: 0.214 AC: 65954 AN: 308304

Other (OTH) AF: 0.216 AC: 6035 AN: 27940

GnomAD4 genome AF: 0.229 AC: 34799 AN: 151932 Hom.: 4146 Cov.: 32 AF XY: 0.228 AC XY: 16959 AN XY: 74246

African (AFR) AF: 0.278 AC: 11543 AN: 41454

American (AMR) AF: 0.216 AC: 3287 AN: 15218

Ashkenazi Jewish (ASJ) AF: 0.195 AC: 676 AN: 3462

East Asian (EAS) AF: 0.194 AC: 1000 AN: 5146

South Asian (SAS) AF: 0.238 AC: 1147 AN: 4826

European-Finnish (FIN) AF: 0.205 AC: 2177 AN: 10596

Middle Eastern (MID) AF: 0.282 AC: 83 AN: 294

European-Non Finnish (NFE) AF: 0.209 AC: 14216 AN: 67910

Other (OTH) AF: 0.241 AC: 510 AN: 2114

Alfa AF: 0.207 Hom.: 393

Bravo AF: 0.234

Asia WGS AF: 0.207 AC: 718 AN: 3472

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	2.0
DANN	Benign	0.36
PhyloP100		-0.069
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: rs1029847; hg19: chr7-81593220; COSMIC: COSV62372126; COSMIC: COSV62372126;