3-50370337-G-C

Variant names:

• chr3-50370337-G-C
• rs375385112
• NM_006030.4:c.2028C>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The ENST00000266039.7(CACNA2D2):​c.2028C>G​(p.His676Gln) variant causes a missense change. The variant allele was found at a frequency of 0.000000696 in 1,437,348 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. H676H) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: CACNA2D2 ENST00000266039.7 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.88
• Publications: 0 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

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000266039.7. 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
	CACNA2D2	NM_006030.4	MANE Select	c.2028C>G	p.His676Gln	missense	Exon 23 of 38	NP_006021.2
	CACNA2D2	NM_001174051.3		c.2049C>G	p.His683Gln	missense	Exon 24 of 39	NP_001167522.1
	CACNA2D2	NM_001005505.3		c.2028C>G	p.His676Gln	missense	Exon 23 of 38	NP_001005505.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CACNA2D2	ENST00000424201.7	TSL:1 MANE Select	c.2028C>G	p.His676Gln	missense	Exon 23 of 38	ENSP00000390329.2
	CACNA2D2	ENST00000423994.6	TSL:5	c.2049C>G	p.His683Gln	missense	Exon 24 of 39	ENSP00000407393.2
	CACNA2D2	ENST00000479441.1	TSL:1	c.2049C>G	p.His683Gln	missense	Exon 24 of 39	ENSP00000418081.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.96e-7 AC: 1 AN: 1437348 Hom.: 0 Cov.: 32 AF XY: 0.00000140 AC XY: 1 AN XY: 712512

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 32914

American (AMR) AF: 0.00 AC: 0 AN: 41528

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25710

East Asian (EAS) AF: 0.00 AC: 0 AN: 38416

South Asian (SAS) AF: 0.00 AC: 0 AN: 82576

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50464

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5742

European-Non Finnish (NFE) AF: 9.09e-7 AC: 1 AN: 1100478

Other (OTH) AF: 0.00 AC: 0 AN: 59520

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.73
BayesDel_addAF	Benign	-0.060	T
BayesDel_noAF	Benign	-0.32
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.068	T
Eigen	Benign	0.063
Eigen_PC	Benign	0.062
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Benign	0.84	T
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.41	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		3.9
PrimateAI	Pathogenic	0.87	D
PROVEAN	Benign	-2.3	N
REVEL	Benign	0.21
Sift	Uncertain	0.016	D
Sift4G	Uncertain	0.037	D
Polyphen		0.91	P
Vest4		0.64
MutPred		0.58		Gain of loop (P = 0.1069)
MVP		0.13
MPC		1.3
ClinPred		0.92	D
GERP RS		3.4
Varity_R		0.15
gMVP		0.70
Mutation Taster		=61/39	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.31		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.31		Position offset: -17

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs375385112; hg19: chr3-50407768;