rs72934809

Variant names:

• chr3-50364749-C-T
• rs72934809
• NM_006030.4:c.3349G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001174051.3(CACNA2D2):​c.3370G>A​(p.Val1124Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00638 in 1,567,964 control chromosomes in the GnomAD database, including 569 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.034 (291 hom., cov: 33)
  • Exomes 𝑓: 0.0034 (278 hom.)
• Consequence: CACNA2D2 NM_001174051.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 1.73
• Publications: 2 publications found

Genes affected

CACNA2D2 (HGNC:1400): (calcium voltage-gated channel auxiliary subunit alpha2delta 2) Calcium channels mediate the entry of calcium ions into the cell upon membrane polarization. This gene encodes the alpha-2/delta subunit of the voltage-dependent calcium channel complex. The complex consists of the main channel-forming subunit alpha-1, and auxiliary subunits alpha-2/delta, beta, and gamma. The auxiliary subunits function in the assembly and membrane localization of the complex, and modulate calcium currents and channel activation/inactivation kinetics. The subunit encoded by this gene undergoes post-translational cleavage to yield the extracellular alpha2 peptide and a membrane-anchored delta polypeptide. This subunit is a receptor for the antiepileptic drug, gabapentin. Mutations in this gene are associated with early infantile epileptic encephalopathy. Single nucleotide polymorphisms in this gene are correlated with increased sensitivity to opioid drugs. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Mar 2014]

CACNA2D2 Gene-Disease associations (from GenCC):

• cerebellar atrophy with seizures and variable developmental delay

  Inheritance: AR Classification: STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• complex neurodevelopmental disorder

  Inheritance: AR Classification: MODERATE Submitted by: ClinGen

ENSG00000272104 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0013693869).
• BP6: Variant 3-50364749-C-T is Benign according to our data. Variant chr3-50364749-C-T is described in ClinVar as Benign. ClinVar VariationId is 416537.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.116 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001174051.3. 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
	CACNA2D2	NM_006030.4	MANE Select	c.3349G>A	p.Val1117Ile	missense	Exon 38 of 38	NP_006021.2
	CACNA2D2	NM_001174051.3		c.3370G>A	p.Val1124Ile	missense	Exon 39 of 39	NP_001167522.1
	CACNA2D2	NM_001005505.3		c.3355G>A	p.Val1119Ile	missense	Exon 38 of 38	NP_001005505.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CACNA2D2	ENST00000424201.7	TSL:1 MANE Select	c.3349G>A	p.Val1117Ile	missense	Exon 38 of 38	ENSP00000390329.2
	CACNA2D2	ENST00000423994.6	TSL:5	c.3379G>A	p.Val1127Ile	missense	Exon 39 of 39	ENSP00000407393.2
	CACNA2D2	ENST00000479441.1	TSL:1	c.3370G>A	p.Val1124Ile	missense	Exon 39 of 39	ENSP00000418081.1

Frequencies

GnomAD3 genomes AF: 0.0341 AC: 5195 AN: 152166 Hom.: 290 Cov.: 33

Gnomad AFR AF: 0.118

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0145

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000294

Gnomad OTH AF: 0.0206

GnomAD2 exomes AF: 0.00737 AC: 1316 AN: 178616 AF XY: 0.00525

Gnomad AFR exome AF: 0.117

Gnomad AMR exome AF: 0.00430

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000136

Gnomad OTH exome AF: 0.00433

GnomAD4 exome AF: 0.00339 AC: 4797 AN: 1415680 Hom.: 278 Cov.: 33 AF XY: 0.00281 AC XY: 1969 AN XY: 700662

African (AFR) AF: 0.127 AC: 4063 AN: 31976

American (AMR) AF: 0.00517 AC: 195 AN: 37696

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25372

East Asian (EAS) AF: 0.00 AC: 0 AN: 36424

South Asian (SAS) AF: 0.000392 AC: 32 AN: 81666

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49338

Middle Eastern (MID) AF: 0.00173 AC: 9 AN: 5200

European-Non Finnish (NFE) AF: 0.0000606 AC: 66 AN: 1089424

Other (OTH) AF: 0.00737 AC: 432 AN: 58584

GnomAD4 genome AF: 0.0342 AC: 5210 AN: 152284 Hom.: 291 Cov.: 33 AF XY: 0.0329 AC XY: 2449 AN XY: 74466

African (AFR) AF: 0.118 AC: 4920 AN: 41538

American (AMR) AF: 0.0144 AC: 221 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00124 AC: 6 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000294 AC: 20 AN: 68024

Other (OTH) AF: 0.0204 AC: 43 AN: 2110

Alfa AF: 0.0126 Hom.: 55

Bravo AF: 0.0387

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.107 AC: 464

ESP6500EA AF: 0.000588 AC: 5

ExAC AF: 0.00808 AC: 954

Asia WGS AF: 0.00635 AC: 23 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Developmental and epileptic encephalopathy (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.74	T
BayesDel_noAF	Benign	-0.74
CADD	Benign	18
DANN	Benign	0.95
DEOGEN2	Benign	0.0064	T
Eigen	Benign	-0.62
Eigen_PC	Benign	-0.42
FATHMM_MKL	Benign	0.67	D
LIST_S2	Benign	0.70	T
MetaRNN	Benign	0.0014	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	0.0	N
PhyloP100		1.7
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	0.19	N
REVEL	Benign	0.061
Sift	Benign	0.94	T
Sift4G	Benign	0.68	T
Polyphen		0.0	B
Vest4		0.15
MVP		0.068
MPC		0.52
ClinPred		0.013	T
GERP RS		2.7
Varity_R		0.025
gMVP		0.55
Mutation Taster		=97/3	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: rs72934809; hg19: chr3-50402180;