rs77176698

Variant names:

• chr3-50364729-G-A
• rs77176698
• NM_006030.4:c.3369C>T

Your query was ambiguous. Multiple possible variants found:

• chr3-50364729-G-A
• chr3-50364729-G-C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_006030.4(CACNA2D2):​c.3369C>T​(p.Leu1123Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000563 in 1,556,744 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. L1123L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0031 (3 hom., cov: 33)
  • Exomes 𝑓: 0.00029 (3 hom.)
• Consequence: CACNA2D2 NM_006030.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.579
• Publications: 1 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.5).
• BP6: Variant 3-50364729-G-A is Benign according to our data. Variant chr3-50364729-G-A is described in ClinVar as Benign. ClinVar VariationId is 416544.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.579 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0031 (472/152364) while in subpopulation AFR AF = 0.011 (457/41584). AF 95% confidence interval is 0.0102. There are 3 homozygotes in GnomAd4. There are 217 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 3 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006030.4. 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
	CACNA2D2	NM_006030.4	MANE Select	c.3369C>T	p.Leu1123Leu	synonymous	Exon 38 of 38	NP_006021.2	Q9NY47-2
	CACNA2D2	NM_001174051.3		c.3390C>T	p.Leu1130Leu	synonymous	Exon 39 of 39	NP_001167522.1	Q9NY47-1
	CACNA2D2	NM_001005505.3		c.3375C>T	p.Leu1125Leu	synonymous	Exon 38 of 38	NP_001005505.1	Q9NY47-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CACNA2D2	ENST00000424201.7	TSL:1 MANE Select	c.3369C>T	p.Leu1123Leu	synonymous	Exon 38 of 38	ENSP00000390329.2	Q9NY47-2
	CACNA2D2	ENST00000423994.6	TSL:5	c.3399C>T	p.Leu1133Leu	synonymous	Exon 39 of 39	ENSP00000407393.2	C9JVC9
	CACNA2D2	ENST00000479441.1	TSL:1	c.3390C>T	p.Leu1130Leu	synonymous	Exon 39 of 39	ENSP00000418081.1	Q9NY47-1

Frequencies

GnomAD3 genomes AF: 0.00310 AC: 472 AN: 152246 Hom.: 3 Cov.: 33

Gnomad AFR AF: 0.0110

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000523

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.000593 AC: 98 AN: 165242 AF XY: 0.000385

Gnomad AFR exome AF: 0.00935

Gnomad AMR exome AF: 0.000395

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000304

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000288 AC: 404 AN: 1404380 Hom.: 3 Cov.: 33 AF XY: 0.000257 AC XY: 178 AN XY: 693776

African (AFR) AF: 0.0112 AC: 354 AN: 31662

American (AMR) AF: 0.000387 AC: 14 AN: 36216

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25214

East Asian (EAS) AF: 0.0000278 AC: 1 AN: 35914

South Asian (SAS) AF: 0.0000124 AC: 1 AN: 80602

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48700

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4874

European-Non Finnish (NFE) AF: 0.00000923 AC: 10 AN: 1083030

Other (OTH) AF: 0.000413 AC: 24 AN: 58168

GnomAD4 genome AF: 0.00310 AC: 472 AN: 152364 Hom.: 3 Cov.: 33 AF XY: 0.00291 AC XY: 217 AN XY: 74508

African (AFR) AF: 0.0110 AC: 457 AN: 41584

American (AMR) AF: 0.000522 AC: 8 AN: 15312

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

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

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68032

Other (OTH) AF: 0.00236 AC: 5 AN: 2116

Alfa AF: 0.000796 Hom.: 0

Bravo AF: 0.00328

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.50
CADD	Benign	1.9
DANN	Benign	0.95
PhyloP100		-0.58

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: rs77176698; hg19: chr3-50402160;