chr7-81970737-G-C

Variant names:

• chr7-81970737-G-C
• rs745501384
• NM_000722.4:c.2142C>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_000722.4(CACNA2D1):​c.2142C>G​(p.Ile714Met) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000635 in 1,417,430 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. I714I) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000063 (0 hom.)
• Consequence: CACNA2D1 NM_000722.4 missense, splice_region
• Scores: Splicing: ADA: 0.0004352
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: -0.0530
• Publications: 2 publications found

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 Gene-Disease associations (from GenCC):

• short QT syndrome

  Inheritance: AD Classification: SUPPORTIVE, NO_KNOWN Submitted by: ClinGen, Orphanet
• Brugada syndrome

  Inheritance: AD, Unknown Classification: LIMITED, NO_KNOWN Submitted by: Ambry Genetics, Genomics England PanelApp
• genetic developmental and epileptic encephalopathy

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
• developmental and epileptic encephalopathy 110

  Inheritance: AR Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae), G2P
• Brugada syndrome 1

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.12787518).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000722.4. 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
	CACNA2D1	NM_000722.4	MANE Select	c.2142C>G	p.Ile714Met	missense splice_region	Exon 27 of 39	NP_000713.2
	CACNA2D1	NM_001366867.1		c.2178C>G	p.Ile726Met	missense splice_region	Exon 27 of 39	NP_001353796.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CACNA2D1	ENST00000356860.8	TSL:1 MANE Select	c.2142C>G	p.Ile714Met	missense splice_region	Exon 27 of 39	ENSP00000349320.3
	CACNA2D1	ENST00000443883.2	TSL:5	c.2178C>G	p.Ile726Met	missense splice_region	Exon 27 of 39	ENSP00000409374.2
	CACNA2D1	ENST00000705962.1		c.2022C>G	p.Ile674Met	missense splice_region	Exon 26 of 38	ENSP00000516190.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000799 AC: 2 AN: 250334 AF XY: 0.00000739

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000177

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000635 AC: 9 AN: 1417430 Hom.: 0 Cov.: 24 AF XY: 0.00000565 AC XY: 4 AN XY: 707798

African (AFR) AF: 0.00 AC: 0 AN: 32516

American (AMR) AF: 0.00 AC: 0 AN: 44596

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25744

East Asian (EAS) AF: 0.00 AC: 0 AN: 39364

South Asian (SAS) AF: 0.0000117 AC: 1 AN: 85382

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53350

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5684

European-Non Finnish (NFE) AF: 0.00000746 AC: 8 AN: 1071978

Other (OTH) AF: 0.00 AC: 0 AN: 58816

GnomAD4 genome Cov.: 32

ExAC AF: 0.0000165 AC: 2

EpiCase AF: 0.000218

EpiControl AF: 0.000119

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Brugada syndrome Uncertain:1

Jan 05, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces isoleucine with methionine at codon 714 of the CACNA2D1 protein (p.Ile714Met). The isoleucine residue is weakly conserved and there is a small physicochemical difference between isoleucine and methionine. 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 are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Not Available"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals with CACNA2D1-related conditions. ClinVar contains an entry for this variant (Variation ID: 411090). This variant is present in population databases (rs745501384, ExAC 0.003%).

Cardiovascular phenotype Uncertain:1

Nov 27, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.I714M variant (also known as c.2142C>G) is located in coding exon 27 of the CACNA2D1 gene. The isoleucine at codon 714 is replaced by methionine, an amino acid with highly similar properties. This change occurs in the first base pair of coding exon 27. This amino acid position is conserved. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.090
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	18
DANN	Uncertain	0.98
DEOGEN2	Benign	0.041	T
Eigen	Benign	0.13
Eigen_PC	Benign	0.12
FATHMM_MKL	Benign	0.41	N
LIST_S2	Benign	0.59	T
MetaRNN	Benign	0.13	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.34	N
PhyloP100		-0.053
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-0.080	N
REVEL	Benign	0.15
Sift	Benign	0.12	T
Sift4G	Benign	0.27	T
Polyphen		0.21	B
Vest4		0.074
MutPred		0.54		Loss of sheet (P = 0.0126)
MVP		0.32
MPC		0.57
ClinPred		0.076	T
GERP RS		3.6
Varity_R		0.064
gMVP		0.42
Mutation Taster		=72/28	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00044
dbscSNV1_RF	Benign	0.10
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: rs745501384; hg19: chr7-81600053;