NM_000722.4:c.355-5dupT

Variant names:

• chr7-82136680-C-CA
• rs142849270
• NM_000722.4:c.355-5dupT

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.355-5dupT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.102 in 1,238,188 control chromosomes in the GnomAD database, including 1,593 homozygotes. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.10 (782 hom., cov: 30)
  • Exomes 𝑓: 0.10 (811 hom.)
• Consequence: CACNA2D1 NM_000722.4 splice_region, intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.0210
• Publications: 1 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 -16 ACMG points.

• BP6: Variant 7-82136680-C-CA is Benign according to our data. Variant chr7-82136680-C-CA is described in ClinVar as Benign. ClinVar VariationId is 215477.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.148 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA2D1	NM_000722.4	c.355-5dupT		splice_region_variant, intron_variant	Intron 4 of 38	ENST00000356860.8	NP_000713.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA2D1	ENST00000356860.8	c.355-5_355-4insT		splice_region_variant, intron_variant	Intron 4 of 38	1	NM_000722.4	ENSP00000349320.3

Frequencies

GnomAD3 genomes AF: 0.103 AC: 14369 AN: 139096 Hom.: 775 Cov.: 30

Gnomad AFR AF: 0.151

Gnomad AMI AF: 0.0708

Gnomad AMR AF: 0.108

Gnomad ASJ AF: 0.112

Gnomad EAS AF: 0.110

Gnomad SAS AF: 0.0939

Gnomad FIN AF: 0.0694

Gnomad MID AF: 0.225

Gnomad NFE AF: 0.0777

Gnomad OTH AF: 0.104

GnomAD2 exomes AF: 0.136 AC: 15821 AN: 116500 AF XY: 0.131

Gnomad AFR exome AF: 0.195

Gnomad AMR exome AF: 0.200

Gnomad ASJ exome AF: 0.156

Gnomad EAS exome AF: 0.168

Gnomad FIN exome AF: 0.102

Gnomad NFE exome AF: 0.110

Gnomad OTH exome AF: 0.139

GnomAD4 exome AF: 0.102 AC: 112000 AN: 1099000 Hom.: 811 Cov.: 25 AF XY: 0.101 AC XY: 55093 AN XY: 543618

African (AFR) AF: 0.171 AC: 4328 AN: 25290

American (AMR) AF: 0.143 AC: 4245 AN: 29636

Ashkenazi Jewish (ASJ) AF: 0.130 AC: 2412 AN: 18530

East Asian (EAS) AF: 0.152 AC: 4315 AN: 28480

South Asian (SAS) AF: 0.102 AC: 6076 AN: 59772

European-Finnish (FIN) AF: 0.0768 AC: 2648 AN: 34466

Middle Eastern (MID) AF: 0.171 AC: 781 AN: 4562

European-Non Finnish (NFE) AF: 0.0964 AC: 82295 AN: 853622

Other (OTH) AF: 0.110 AC: 4900 AN: 44642

GnomAD4 genome AF: 0.103 AC: 14399 AN: 139188 Hom.: 782 Cov.: 30 AF XY: 0.104 AC XY: 6961 AN XY: 67244

African (AFR) AF: 0.151 AC: 5770 AN: 38220

American (AMR) AF: 0.108 AC: 1485 AN: 13764

Ashkenazi Jewish (ASJ) AF: 0.112 AC: 369 AN: 3282

East Asian (EAS) AF: 0.110 AC: 532 AN: 4832

South Asian (SAS) AF: 0.0931 AC: 408 AN: 4382

European-Finnish (FIN) AF: 0.0694 AC: 571 AN: 8224

Middle Eastern (MID) AF: 0.241 AC: 67 AN: 278

European-Non Finnish (NFE) AF: 0.0777 AC: 4926 AN: 63418

Other (OTH) AF: 0.109 AC: 209 AN: 1912

Alfa AF: 0.0572 Hom.: 11

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Brugada syndrome Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

Jun 11, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.021
Mutation Taster		=100/0	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: rs142849270; hg19: chr7-81765996; COSMIC: COSV62374198;