7-81974555-GAAAA-GAAAAAA

Variant names:

• chr7-81974555-G-GAA
• rs3083235
• NM_000722.4:c.1956-5_1956-4dupTT

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_000722.4(CACNA2D1):​c.1956-5_1956-4dupTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0775 in 1,342,172 control chromosomes in the GnomAD database, including 3,164 homozygotes. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.092 (630 hom., cov: 30)
  • Exomes 𝑓: 0.076 (2534 hom.)
• Consequence: CACNA2D1 NM_000722.4 splice_region, intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• 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
• 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

  Inheritance: Unknown, AD Classification: LIMITED, NO_KNOWN Submitted by: Genomics England PanelApp, Ambry Genetics
• Brugada syndrome 1

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -16 ACMG points.

• BP6: Variant 7-81974555-G-GAA is Benign according to our data. Variant chr7-81974555-G-GAA is described in ClinVar as Benign. ClinVar VariationId is 215475.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.108 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.1956-5_1956-4dupTT		splice_region intron	N/A	NP_000713.2	P54289-2
	CACNA2D1	NM_001366867.1		c.1992-5_1992-4dupTT		splice_region 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.1956-4_1956-3insTT		splice_region intron	N/A	ENSP00000349320.3	P54289-2
	CACNA2D1	ENST00000443883.2	TSL:5	c.1992-4_1992-3insTT		splice_region intron	N/A	ENSP00000409374.2	H0Y715
	CACNA2D1	ENST00000957014.1		c.1977-4_1977-3insTT		splice_region intron	N/A	ENSP00000627073.1

Frequencies

GnomAD3 genomes AF: 0.0923 AC: 13610 AN: 147442 Hom.: 631 Cov.: 30

Gnomad AFR AF: 0.0940

Gnomad AMI AF: 0.148

Gnomad AMR AF: 0.111

Gnomad ASJ AF: 0.0990

Gnomad EAS AF: 0.115

Gnomad SAS AF: 0.0623

Gnomad FIN AF: 0.0428

Gnomad MID AF: 0.192

Gnomad NFE AF: 0.0921

Gnomad OTH AF: 0.122

GnomAD2 exomes AF: 0.0885 AC: 17192 AN: 194206 AF XY: 0.0857

Gnomad AFR exome AF: 0.0933

Gnomad AMR exome AF: 0.118

Gnomad ASJ exome AF: 0.0995

Gnomad EAS exome AF: 0.113

Gnomad FIN exome AF: 0.0417

Gnomad NFE exome AF: 0.0908

Gnomad OTH exome AF: 0.0985

GnomAD4 exome AF: 0.0756 AC: 90358 AN: 1194648 Hom.: 2534 Cov.: 18 AF XY: 0.0749 AC XY: 45272 AN XY: 604160

African (AFR) AF: 0.0825 AC: 2274 AN: 27552

American (AMR) AF: 0.107 AC: 4447 AN: 41398

Ashkenazi Jewish (ASJ) AF: 0.0946 AC: 2222 AN: 23492

East Asian (EAS) AF: 0.0925 AC: 3388 AN: 36620

South Asian (SAS) AF: 0.0533 AC: 4095 AN: 76820

European-Finnish (FIN) AF: 0.0405 AC: 2029 AN: 50076

Middle Eastern (MID) AF: 0.142 AC: 685 AN: 4820

European-Non Finnish (NFE) AF: 0.0759 AC: 67048 AN: 883336

Other (OTH) AF: 0.0825 AC: 4170 AN: 50534

GnomAD4 genome AF: 0.0923 AC: 13615 AN: 147524 Hom.: 630 Cov.: 30 AF XY: 0.0901 AC XY: 6466 AN XY: 71738

African (AFR) AF: 0.0940 AC: 3774 AN: 40160

American (AMR) AF: 0.110 AC: 1629 AN: 14758

Ashkenazi Jewish (ASJ) AF: 0.0990 AC: 342 AN: 3456

East Asian (EAS) AF: 0.116 AC: 584 AN: 5050

South Asian (SAS) AF: 0.0620 AC: 289 AN: 4658

European-Finnish (FIN) AF: 0.0428 AC: 400 AN: 9342

Middle Eastern (MID) AF: 0.196 AC: 56 AN: 286

European-Non Finnish (NFE) AF: 0.0921 AC: 6159 AN: 66860

Other (OTH) AF: 0.121 AC: 248 AN: 2050

Alfa AF: 0.0417 Hom.: 35

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.20
Mutation Taster		=100/0	polymorphism (auto)

Splicing

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: COSV62393396; COSMIC: COSV62393396;