chr7-82066526-T-TA

Variant names:

• chr7-82066526-T-TA
• rs370103843
• NM_000722.4:c.659-3dupT

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.659-3dupT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0759 in 1,429,314 control chromosomes in the GnomAD database, including 1,400 homozygotes. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.15 (1394 hom., cov: 27)
  • Exomes 𝑓: 0.070 (6 hom.)
• Consequence: CACNA2D1 NM_000722.4 splice_region, intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• 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: Benign. The variant received -16 ACMG points.

• BP6: Variant 7-82066526-T-TA is Benign according to our data. Variant chr7-82066526-T-TA is described in ClinVar as Benign. ClinVar VariationId is 416577.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.257 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.659-3dupT		splice_region intron	N/A	NP_000713.2	P54289-2
	CACNA2D1	NM_001366867.1		c.659-3dupT		splice_region intron	N/A	NP_001353796.1	P54289-1
	CACNA2D1	NM_001302890.2		c.659-3dupT		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_659-2insT		splice_region intron	N/A	ENSP00000349320.3	P54289-2
	CACNA2D1	ENST00000423588.1	TSL:1	c.659-3_659-2insT		splice_region intron	N/A	ENSP00000405395.1	E7ERK3
	CACNA2D1	ENST00000443883.2	TSL:5	c.659-3_659-2insT		splice_region intron	N/A	ENSP00000409374.2	H0Y715

Frequencies

GnomAD3 genomes AF: 0.150 AC: 16760 AN: 111620 Hom.: 1392 Cov.: 27

Gnomad AFR AF: 0.262

Gnomad AMI AF: 0.203

Gnomad AMR AF: 0.118

Gnomad ASJ AF: 0.114

Gnomad EAS AF: 0.129

Gnomad SAS AF: 0.108

Gnomad FIN AF: 0.0499

Gnomad MID AF: 0.259

Gnomad NFE AF: 0.0968

Gnomad OTH AF: 0.160

GnomAD2 exomes AF: 0.0596 AC: 5397 AN: 90532 AF XY: 0.0588

Gnomad AFR exome AF: 0.109

Gnomad AMR exome AF: 0.0458

Gnomad ASJ exome AF: 0.0642

Gnomad EAS exome AF: 0.0677

Gnomad FIN exome AF: 0.0420

Gnomad NFE exome AF: 0.0574

Gnomad OTH exome AF: 0.0665

GnomAD4 exome AF: 0.0696 AC: 91684 AN: 1317716 Hom.: 6 Cov.: 0 AF XY: 0.0685 AC XY: 44591 AN XY: 651366

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

African (AFR) AF: 0.166 AC: 4606 AN: 27686

American (AMR) AF: 0.0463 AC: 1384 AN: 29884

Ashkenazi Jewish (ASJ) AF: 0.0697 AC: 1627 AN: 23344

East Asian (EAS) AF: 0.0690 AC: 2410 AN: 34948

South Asian (SAS) AF: 0.0632 AC: 4382 AN: 69328

European-Finnish (FIN) AF: 0.0395 AC: 1548 AN: 39144

Middle Eastern (MID) AF: 0.0998 AC: 410 AN: 4108

European-Non Finnish (NFE) AF: 0.0689 AC: 71310 AN: 1034928

Other (OTH) AF: 0.0737 AC: 4007 AN: 54346

⚠️ 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: 0.150 AC: 16763 AN: 111598 Hom.: 1394 Cov.: 27 AF XY: 0.149 AC XY: 7871 AN XY: 52906

African (AFR) AF: 0.262 AC: 8833 AN: 33768

American (AMR) AF: 0.117 AC: 1231 AN: 10480

Ashkenazi Jewish (ASJ) AF: 0.114 AC: 298 AN: 2610

East Asian (EAS) AF: 0.130 AC: 501 AN: 3866

South Asian (SAS) AF: 0.108 AC: 376 AN: 3478

European-Finnish (FIN) AF: 0.0499 AC: 256 AN: 5130

Middle Eastern (MID) AF: 0.267 AC: 54 AN: 202

European-Non Finnish (NFE) AF: 0.0968 AC: 4824 AN: 49820

Other (OTH) AF: 0.160 AC: 244 AN: 1526

Alfa AF: 0.0244 Hom.: 11

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.0
Mutation Taster		=98/2	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: rs370103843; hg19: chr7-81695842; COSMIC: COSV62375507;