7-81950456-T-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_000722.4(CACNA2D1):c.3212A>C(p.Tyr1071Ser) 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. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y1071H) has been classified 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: 3.10

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]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.03557694).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CACNA2D1	NM_000722.4	c.3212A>C	p.Tyr1071Ser	missense_variant	39/39	ENST00000356860.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CACNA2D1	ENST00000356860.8	c.3212A>C	p.Tyr1071Ser	missense_variant	39/39	1	NM_000722.4
CACNA2D1	ENST00000443883.2	c.3248A>C	p.Tyr1083Ser	missense_variant	39/39	5		P1
CACNA2D1	ENST00000705962.1	c.3092A>C	p.Tyr1031Ser	missense_variant	38/38
CACNA2D1	ENST00000705961.1	c.2981A>C	p.Tyr994Ser	missense_variant	37/37

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

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

Invitae

Nov 20, 2023

This sequence change replaces tyrosine, which is neutral and polar, with serine, which is neutral and polar, at codon 1071 of the CACNA2D1 protein (p.Tyr1071Ser). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with CACNA2D1-related conditions. ClinVar contains an entry for this variant (Variation ID: 1505740). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The serine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.041
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.67
Cadd	Benign	9.0
Dann	Benign	0.27
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.71	T;T
M_CAP	Benign	0.0023	T
MetaRNN	Benign	0.036	T;T
MetaSVM	Benign	-0.97	T
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.39	T
PROVEAN	Benign	0.99	N;N
REVEL	Benign	0.080
Sift	Benign	0.65	T;T
Sift4G	Benign	0.22	T;T
Polyphen		0.0	B;.
Vest4		0.13
MVP		0.043
MPC		0.65
ClinPred		0.12	T
GERP RS		2.1
Varity_R		0.048
gMVP		0.70

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr7-81579772;