7-82066526-TAAAAAAA-TAAAAAAAAA

Variant names:

• chr7-82066526-T-TAA
• rs370103843
• NM_000722.4:c.659-4_659-3dupTT

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP6_Moderate BS2

The NM_000722.4(CACNA2D1):​c.659-4_659-3dupTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00571 in 1,444,058 control chromosomes in the GnomAD database, including 7 homozygotes. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0073 (5 hom., cov: 27)
  • Exomes 𝑓: 0.0056 (2 hom.)
• Consequence: CACNA2D1 NM_000722.4 splice_region, intron
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 1.04
• 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: Likely_benign. The variant received -6 ACMG points.

• BP6: Variant 7-82066526-T-TAA is Benign according to our data. Variant chr7-82066526-T-TAA is described in ClinVar as Likely_benign. ClinVar VariationId is 1284710.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAd4 at 5 AR,Unknown,AD 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CACNA2D1	NM_000722.4	MANE Select	c.659-4_659-3dupTT		splice_region intron	N/A	NP_000713.2	P54289-2
	CACNA2D1	NM_001366867.1		c.659-4_659-3dupTT		splice_region intron	N/A	NP_001353796.1	P54289-1
	CACNA2D1	NM_001302890.2		c.659-4_659-3dupTT		splice_region intron	N/A	NP_001289819.1	E7ERK3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CACNA2D1	ENST00000356860.8	TSL:1 MANE Select	c.659-3_659-2insTT		splice_region intron	N/A	ENSP00000349320.3	P54289-2
	CACNA2D1	ENST00000423588.1	TSL:1	c.659-3_659-2insTT		splice_region intron	N/A	ENSP00000405395.1	E7ERK3
	CACNA2D1	ENST00000443883.2	TSL:5	c.659-3_659-2insTT		splice_region intron	N/A	ENSP00000409374.2	H0Y715

Frequencies

GnomAD3 genomes AF: 0.00733 AC: 819 AN: 111742 Hom.: 5 Cov.: 27

Gnomad AFR AF: 0.00278

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00477

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000514

Gnomad SAS AF: 0.00656

Gnomad FIN AF: 0.0204

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0106

Gnomad OTH AF: 0.0125

GnomAD2 exomes AF: 0.00556 AC: 503 AN: 90532 AF XY: 0.00589

Gnomad AFR exome AF: 0.00736

Gnomad AMR exome AF: 0.00440

Gnomad ASJ exome AF: 0.00321

Gnomad EAS exome AF: 0.00616

Gnomad FIN exome AF: 0.00637

Gnomad NFE exome AF: 0.00563

Gnomad OTH exome AF: 0.00455

GnomAD4 exome AF: 0.00558 AC: 7428 AN: 1332338 Hom.: 2 Cov.: 0 AF XY: 0.00552 AC XY: 3635 AN XY: 658300

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00368 AC: 104 AN: 28242

American (AMR) AF: 0.00313 AC: 94 AN: 29988

Ashkenazi Jewish (ASJ) AF: 0.00204 AC: 48 AN: 23508

East Asian (EAS) AF: 0.00210 AC: 74 AN: 35222

South Asian (SAS) AF: 0.00616 AC: 430 AN: 69846

European-Finnish (FIN) AF: 0.00772 AC: 303 AN: 39254

Middle Eastern (MID) AF: 0.00386 AC: 16 AN: 4140

European-Non Finnish (NFE) AF: 0.00577 AC: 6048 AN: 1047274

Other (OTH) AF: 0.00567 AC: 311 AN: 54864

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00732 AC: 818 AN: 111720 Hom.: 5 Cov.: 27 AF XY: 0.00774 AC XY: 410 AN XY: 52974

African (AFR) AF: 0.00281 AC: 95 AN: 33832

American (AMR) AF: 0.00477 AC: 50 AN: 10482

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2614

East Asian (EAS) AF: 0.000517 AC: 2 AN: 3870

South Asian (SAS) AF: 0.00603 AC: 21 AN: 3484

European-Finnish (FIN) AF: 0.0204 AC: 105 AN: 5144

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 202

European-Non Finnish (NFE) AF: 0.0106 AC: 526 AN: 49844

Other (OTH) AF: 0.0124 AC: 19 AN: 1530

Alfa AF: 0.00265 Hom.: 11

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.0
Mutation Taster		=100/0	polymorphism

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs370103843; hg19: chr7-81695842;