7-81974555-GAAAA-GAAA

Variant names:

• chr7-81974555-GA-G
• rs3083235
• NM_000722.4:c.1956-4delT

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP6_Very_Strong BS2

The NM_000722.4(CACNA2D1):​c.1956-4delT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000556 in 1,344,872 control chromosomes in the GnomAD database, including 4 homozygotes. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0025 (2 hom., cov: 30)
  • Exomes 𝑓: 0.00032 (2 hom.)
• Consequence: CACNA2D1 NM_000722.4 splice_region, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.195
• Publications: 3 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.

• BP6: Variant 7-81974555-GA-G is Benign according to our data. Variant chr7-81974555-GA-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 416578.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAd4 at 2 AD,AR,Unknown gene

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CACNA2D1	NM_000722.4	MANE Select	c.1956-4delT		splice_region intron	N/A	NP_000713.2
	CACNA2D1	NM_001366867.1		c.1992-4delT		splice_region intron	N/A	NP_001353796.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CACNA2D1	ENST00000356860.8	TSL:1 MANE Select	c.1956-4delT		splice_region intron	N/A	ENSP00000349320.3
	CACNA2D1	ENST00000443883.2	TSL:5	c.1992-4delT		splice_region intron	N/A	ENSP00000409374.2
	CACNA2D1	ENST00000705962.1		c.1836-4delT		splice_region intron	N/A	ENSP00000516190.1

Frequencies

GnomAD3 genomes AF: 0.00247 AC: 364 AN: 147524 Hom.: 2 Cov.: 30

Gnomad AFR AF: 0.00719

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00441

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000197

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000299

Gnomad OTH AF: 0.00394

GnomAD2 exomes AF: 0.000814 AC: 158 AN: 194206 AF XY: 0.000589

Gnomad AFR exome AF: 0.00916

Gnomad AMR exome AF: 0.00122

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000704

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000701

Gnomad OTH exome AF: 0.000845

GnomAD4 exome AF: 0.000318 AC: 381 AN: 1197266 Hom.: 2 Cov.: 18 AF XY: 0.000282 AC XY: 171 AN XY: 605532

African (AFR) AF: 0.00764 AC: 211 AN: 27624

American (AMR) AF: 0.00139 AC: 58 AN: 41744

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23578

East Asian (EAS) AF: 0.0000545 AC: 2 AN: 36696

South Asian (SAS) AF: 0.0000779 AC: 6 AN: 77034

European-Finnish (FIN) AF: 0.0000399 AC: 2 AN: 50162

Middle Eastern (MID) AF: 0.000619 AC: 3 AN: 4848

European-Non Finnish (NFE) AF: 0.0000542 AC: 48 AN: 884924

Other (OTH) AF: 0.00101 AC: 51 AN: 50656

GnomAD4 genome AF: 0.00249 AC: 367 AN: 147606 Hom.: 2 Cov.: 30 AF XY: 0.00202 AC XY: 145 AN XY: 71768

African (AFR) AF: 0.00724 AC: 291 AN: 40182

American (AMR) AF: 0.00440 AC: 65 AN: 14766

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3458

East Asian (EAS) AF: 0.000198 AC: 1 AN: 5050

South Asian (SAS) AF: 0.00 AC: 0 AN: 4662

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9350

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 286

European-Non Finnish (NFE) AF: 0.0000299 AC: 2 AN: 66896

Other (OTH) AF: 0.00390 AC: 8 AN: 2052

Alfa AF: 0.000258 Hom.: 35

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.20
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs3083235; hg19: chr7-81603871; COSMIC: COSV100667342; COSMIC: COSV100667342;