rs1554333986

Positions:

• chr7-81971848-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000722.4(CACNA2D1):​c.2070T>G​(p.Ile690Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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 Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CACNA2D1 NM_000722.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.724

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.16941085).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA2D1	NM_000722.4	c.2070T>G	p.Ile690Met	missense_variant	26/39	ENST00000356860.8	NP_000713.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA2D1	ENST00000356860.8	c.2070T>G	p.Ile690Met	missense_variant	26/39	1	NM_000722.4	ENSP00000349320.3
CACNA2D1	ENST00000443883.2	c.2106T>G	p.Ile702Met	missense_variant	26/39	5		ENSP00000409374.2
CACNA2D1	ENST00000705962.1	c.1950T>G	p.Ile650Met	missense_variant	25/38			ENSP00000516190.1
CACNA2D1	ENST00000705961.1	c.1836T>G	p.Ile612Met	missense_variant	24/37			ENSP00000516189.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Brugada syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 22, 2017

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with CACNA2D1-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change replaces isoleucine with methionine at codon 690 of the CACNA2D1 protein (p.Ile690Met). The isoleucine residue is weakly conserved and there is a small physicochemical difference between isoleucine and methionine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	20
DANN	Benign	0.94
DEOGEN2	Benign	0.090	.;T
Eigen	Benign	-0.0037
Eigen_PC	Benign	0.11
FATHMM_MKL	Benign	0.73	D
LIST_S2	Uncertain	0.93	D;D
M_CAP	Benign	0.0084	T
MetaRNN	Benign	0.17	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.55	.;N
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-1.2	N;N
REVEL	Benign	0.13
Sift	Benign	0.048	D;D
Sift4G	Benign	0.12	T;T
Polyphen		0.24	B;.
Vest4		0.25
MutPred		0.44		Loss of catalytic residue at L695 (P = 0.0589);.;
MVP		0.15
MPC		0.48
ClinPred		0.47	T
GERP RS		4.1
Varity_R		0.12
gMVP		0.68

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

Publications

LitVar

Other links and lift over

dbSNP: rs1554333986; hg19: chr7-81601164;