rs151327713

chr7-81969925-C-G

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_000722.4(CACNA2D1):c.2264G>C(p.Ser755Thr) variant causes a missense change. The variant allele was found at a frequency of 0.000635 in 1,608,622 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00066 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00063 (2 hom.)
• Consequence: CACNA2D1 NM_000722.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 5.89

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 Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.011730015).
• BP6: Variant 7-81969925-C-G is Benign according to our data. Variant chr7-81969925-C-G is described in ClinVar as [Benign]. Clinvar id is 180288.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-81969925-C-G is described in Lovd as [Likely_benign].
• BS2: High AC in GnomAd at 100 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CACNA2D1	NM_000722.4	c.2264G>C	p.Ser755Thr	missense_variant	28/39	ENST00000356860.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CACNA2D1	ENST00000356860.8	c.2264G>C	p.Ser755Thr	missense_variant	28/39	1	NM_000722.4

Frequencies

GnomAD3 genomes AF: 0.000661 AC: 100 AN: 151300 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.0000968

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000265

Gnomad ASJ AF: 0.0127

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000622

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000652

Gnomad OTH AF: 0.000481

GnomAD3 exomes AF: 0.000924 AC: 231 AN: 250028 Hom.: 2 AF XY: 0.000895 AC XY: 121 AN XY: 135162

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000756

Gnomad ASJ exome AF: 0.0107

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000425

Gnomad FIN exome AF: 0.0000464

Gnomad NFE exome AF: 0.000691

Gnomad OTH exome AF: 0.000987

GnomAD4 exome AF: 0.000632 AC: 921 AN: 1457204 Hom.: 2 Cov.: 29 AF XY: 0.000662 AC XY: 480 AN XY: 725078

Gnomad4 AFR exome AF: 0.0000300

Gnomad4 AMR exome AF: 0.000853

Gnomad4 ASJ exome AF: 0.0101

Gnomad4 EAS exome AF: 0.0000253

Gnomad4 SAS exome AF: 0.000569

Gnomad4 FIN exome AF: 0.0000188

Gnomad4 NFE exome AF: 0.000457

Gnomad4 OTH exome AF: 0.000948

GnomAD4 genome AF: 0.000660 AC: 100 AN: 151418 Hom.: 1 Cov.: 32 AF XY: 0.000594 AC XY: 44 AN XY: 74048

Gnomad4 AFR AF: 0.0000965

Gnomad4 AMR AF: 0.000264

Gnomad4 ASJ AF: 0.0127

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000622

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000652

Gnomad4 OTH AF: 0.000476

Alfa AF: 0.00171 Hom.: 0

Bravo AF: 0.000706

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00105 AC: 9

ExAC AF: 0.000766 AC: 93

EpiCase AF: 0.00148

EpiControl AF: 0.000830

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Cardiac arrest Benign:1

Likely benign, no assertion criteria provided

clinical testing

Blueprint Genetics

Dec 05, 2014

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Apr 15, 2019

This variant is associated with the following publications: (PMID: 25527503, 21383000, 22840528, 29016797, 30847666) -

Brugada syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Dec 26, 2023

- -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 10, 2017

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.33
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Uncertain	-0.030
Cadd	Benign	22
Dann	Uncertain	0.99
Eigen	Uncertain	0.35
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.86	D;D
M_CAP	Benign	0.020	T
MetaRNN	Benign	0.012	T;T
MetaSVM	Benign	-0.41	T
MutationTaster	Benign	0.97	D;D;D
PrimateAI	Uncertain	0.72	T
PROVEAN	Benign	-1.4	N;N
REVEL	Uncertain	0.33
Sift	Benign	0.092	T;T
Sift4G	Benign	0.088	T;T
Polyphen		0.43	B;.
Vest4		0.60
MVP		0.48
MPC		0.51
ClinPred		0.022	T
GERP RS		5.8
Varity_R		0.26
gMVP		0.92

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: rs151327713; hg19: chr7-81599241; COSMIC: COSV99069070;