chr7-82066526-TAAAA-T

Variant names:

• chr7-82066526-TAAAA-T
• rs370103843
• NM_000722.4:c.659-6_659-3delTTTT

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_000722.4(CACNA2D1):​c.659-6_659-3delTTTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000256 in 1,445,984 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.000036 (0 hom., cov: 27)
  • Exomes 𝑓: 0.00027 (0 hom.)
• Consequence: CACNA2D1 NM_000722.4 splice_region, intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.51
• 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: Uncertain_significance. The variant received 0 ACMG points.

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.659-6_659-3delTTTT		splice_region intron	N/A	NP_000713.2	P54289-2
	CACNA2D1	NM_001366867.1		c.659-6_659-3delTTTT		splice_region intron	N/A	NP_001353796.1	P54289-1
	CACNA2D1	NM_001302890.2		c.659-6_659-3delTTTT		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.659-6_659-3delTTTT		splice_region intron	N/A	ENSP00000349320.3	P54289-2
	CACNA2D1	ENST00000423588.1	TSL:1	c.659-6_659-3delTTTT		splice_region intron	N/A	ENSP00000405395.1	E7ERK3
	CACNA2D1	ENST00000443883.2	TSL:5	c.659-6_659-3delTTTT		splice_region intron	N/A	ENSP00000409374.2	H0Y715

Frequencies

GnomAD3 genomes AF: 0.0000358 AC: 4 AN: 111740 Hom.: 0 Cov.: 27

Gnomad AFR AF: 0.0000592

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000195

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000201

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00173 AC: 157 AN: 90532 AF XY: 0.00157

Gnomad AFR exome AF: 0.00294

Gnomad AMR exome AF: 0.00282

Gnomad ASJ exome AF: 0.000857

Gnomad EAS exome AF: 0.00154

Gnomad FIN exome AF: 0.000910

Gnomad NFE exome AF: 0.00167

Gnomad OTH exome AF: 0.00165

GnomAD4 exome AF: 0.000274 AC: 366 AN: 1334244 Hom.: 0 AF XY: 0.000285 AC XY: 188 AN XY: 659102

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

African (AFR) AF: 0.000885 AC: 25 AN: 28248

American (AMR) AF: 0.00154 AC: 46 AN: 29878

Ashkenazi Jewish (ASJ) AF: 0.000426 AC: 10 AN: 23480

East Asian (EAS) AF: 0.000483 AC: 17 AN: 35220

South Asian (SAS) AF: 0.000702 AC: 49 AN: 69794

European-Finnish (FIN) AF: 0.000663 AC: 26 AN: 39196

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4160

European-Non Finnish (NFE) AF: 0.000171 AC: 179 AN: 1049308

Other (OTH) AF: 0.000255 AC: 14 AN: 54960

⚠️ 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: 0.0000358 AC: 4 AN: 111740 Hom.: 0 Cov.: 27 AF XY: 0.0000378 AC XY: 2 AN XY: 52974

African (AFR) AF: 0.0000592 AC: 2 AN: 33790

American (AMR) AF: 0.00 AC: 0 AN: 10478

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 3890

South Asian (SAS) AF: 0.00 AC: 0 AN: 3508

European-Finnish (FIN) AF: 0.000195 AC: 1 AN: 5138

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 220

European-Non Finnish (NFE) AF: 0.0000201 AC: 1 AN: 49858

Other (OTH) AF: 0.00 AC: 0 AN: 1526

Alfa AF: 0.00129 Hom.: 11

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.5

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;