chr7-82382189-G-A

Variant names:

• chr7-82382189-G-A
• rs2299185
• NM_000722.4:c.96-32540C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000722.4(CACNA2D1):​c.96-32540C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.342 in 152,012 control chromosomes in the GnomAD database, including 11,536 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.34 (11536 hom., cov: 32)
• Consequence: CACNA2D1 NM_000722.4 intron
• Clinical Significance: Not reported in ClinVar
• 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.96).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.626 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA2D1	NM_000722.4	c.96-32540C>T		intron_variant	Intron 1 of 38	ENST00000356860.8	NP_000713.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA2D1	ENST00000356860.8	c.96-32540C>T		intron_variant	Intron 1 of 38	1	NM_000722.4	ENSP00000349320.3
CACNA2D1	ENST00000423588.1	c.96-32540C>T		intron_variant	Intron 1 of 10	1		ENSP00000405395.1
CACNA2D1	ENST00000443883.2	c.96-32540C>T		intron_variant	Intron 1 of 38	5		ENSP00000409374.2
CACNA2D1	ENST00000705962.1	c.12-32540C>T		intron_variant	Intron 1 of 37			ENSP00000516190.1

Frequencies

GnomAD3 genomes AF: 0.342 AC: 51918 AN: 151894 Hom.: 11521 Cov.: 32

Gnomad AFR AF: 0.633

Gnomad AMI AF: 0.362

Gnomad AMR AF: 0.294

Gnomad ASJ AF: 0.203

Gnomad EAS AF: 0.169

Gnomad SAS AF: 0.240

Gnomad FIN AF: 0.235

Gnomad MID AF: 0.377

Gnomad NFE AF: 0.220

Gnomad OTH AF: 0.319

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.342 AC: 51985 AN: 152012 Hom.: 11536 Cov.: 32 AF XY: 0.339 AC XY: 25198 AN XY: 74296

African (AFR) AF: 0.633 AC: 26219 AN: 41426

American (AMR) AF: 0.294 AC: 4482 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.203 AC: 706 AN: 3470

East Asian (EAS) AF: 0.170 AC: 876 AN: 5168

South Asian (SAS) AF: 0.240 AC: 1156 AN: 4816

European-Finnish (FIN) AF: 0.235 AC: 2487 AN: 10578

Middle Eastern (MID) AF: 0.384 AC: 113 AN: 294

European-Non Finnish (NFE) AF: 0.220 AC: 14937 AN: 67968

Other (OTH) AF: 0.321 AC: 680 AN: 2116

Alfa AF: 0.263 Hom.: 8317

Bravo AF: 0.359

Asia WGS AF: 0.240 AC: 836 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	2.6
DANN	Benign	0.47
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: rs2299185; hg19: chr7-82011505;