rs10954668

Variant names:

• chr7-82218335-G-A
• rs10954668
• NM_000722.4:c.295-47726C>T

Your query was ambiguous. Multiple possible variants found:

• chr7-82218335-G-A
• chr7-82218335-G-T

Variant summary

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

The ENST00000356860.8(CACNA2D1):​c.295-47726C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.263 in 152,026 control chromosomes in the GnomAD database, including 6,481 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 0.26 (6481 hom., cov: 32)
• Consequence: CACNA2D1 ENST00000356860.8 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.32
• Publications: 10 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=-0.97).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.364 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000356860.8. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CACNA2D1	NM_000722.4	MANE Select	c.295-47726C>T		intron	N/A	NP_000713.2
	CACNA2D1	NM_001366867.1		c.295-47726C>T		intron	N/A	NP_001353796.1
	CACNA2D1	NM_001302890.2		c.295-47726C>T		intron	N/A	NP_001289819.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CACNA2D1	ENST00000356860.8	TSL:1 MANE Select	c.295-47726C>T		intron	N/A	ENSP00000349320.3
	CACNA2D1	ENST00000423588.1	TSL:1	c.295-47726C>T		intron	N/A	ENSP00000405395.1
	CACNA2D1	ENST00000443883.2	TSL:5	c.295-47726C>T		intron	N/A	ENSP00000409374.2

Frequencies

GnomAD3 genomes AF: 0.264 AC: 40032 AN: 151908 Hom.: 6492 Cov.: 32

Gnomad AFR AF: 0.0735

Gnomad AMI AF: 0.351

Gnomad AMR AF: 0.273

Gnomad ASJ AF: 0.396

Gnomad EAS AF: 0.185

Gnomad SAS AF: 0.277

Gnomad FIN AF: 0.292

Gnomad MID AF: 0.364

Gnomad NFE AF: 0.368

Gnomad OTH AF: 0.312

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

GnomAD4 genome AF: 0.263 AC: 40007 AN: 152026 Hom.: 6481 Cov.: 32 AF XY: 0.261 AC XY: 19351 AN XY: 74282

African (AFR) AF: 0.0733 AC: 3040 AN: 41496

American (AMR) AF: 0.273 AC: 4163 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.396 AC: 1375 AN: 3472

East Asian (EAS) AF: 0.184 AC: 953 AN: 5170

South Asian (SAS) AF: 0.277 AC: 1332 AN: 4816

European-Finnish (FIN) AF: 0.292 AC: 3070 AN: 10528

Middle Eastern (MID) AF: 0.364 AC: 107 AN: 294

European-Non Finnish (NFE) AF: 0.368 AC: 24999 AN: 67964

Other (OTH) AF: 0.307 AC: 648 AN: 2110

Alfa AF: 0.326 Hom.: 14704

Bravo AF: 0.254

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
CADD	Benign	0.20
DANN	Benign	0.76
PhyloP100		-1.3
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: rs10954668; hg19: chr7-81847651; COSMIC: COSV62397350;