rs79030053

Positions:

• chr7-82050588-T-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000356860.8(CACNA2D1):​c.879+9840A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0102 in 702,758 control chromosomes in the GnomAD database, including 360 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.032 (254 hom., cov: 32)
  • Exomes 𝑓: 0.0043 (106 hom.)
• Consequence: CACNA2D1 ENST00000356860.8 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.456

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0016416609).
• BP6: Variant 7-82050588-T-A is Benign according to our data. Variant chr7-82050588-T-A is described in ClinVar as [Benign]. Clinvar id is 446965.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-82050588-T-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.107 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA2D1	NM_000722.4	c.879+9840A>T		intron_variant		ENST00000356860.8	NP_000713.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA2D1	ENST00000356860.8	c.879+9840A>T		intron_variant		1	NM_000722.4	ENSP00000349320

Frequencies

GnomAD3 genomes AF: 0.0315 AC: 4787 AN: 152140 Hom.: 249 Cov.: 32

Gnomad AFR AF: 0.109

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0122

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.000456

Gnomad OTH AF: 0.0229

GnomAD3 exomes AF: 0.00672 AC: 919 AN: 136814 Hom.: 49 AF XY: 0.00516 AC XY: 384 AN XY: 74390

Gnomad AFR exome AF: 0.115

Gnomad AMR exome AF: 0.00589

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000178

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000280

Gnomad OTH exome AF: 0.00357

GnomAD4 exome AF: 0.00431 AC: 2372 AN: 550500 Hom.: 106 Cov.: 0 AF XY: 0.00331 AC XY: 987 AN XY: 298024

Gnomad4 AFR exome AF: 0.108

Gnomad4 AMR exome AF: 0.00691

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000159

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000347

Gnomad4 OTH exome AF: 0.00970

GnomAD4 genome AF: 0.0316 AC: 4817 AN: 152258 Hom.: 254 Cov.: 32 AF XY: 0.0302 AC XY: 2252 AN XY: 74472

Gnomad4 AFR AF: 0.110

Gnomad4 AMR AF: 0.0122

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000456

Gnomad4 OTH AF: 0.0227

Alfa AF: 0.0157 Hom.: 24

Bravo AF: 0.0361

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000519 AC: 2

ExAC AF: 0.00508 AC: 94

Asia WGS AF: 0.00779 AC: 27 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jun 23, 2017	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	0.13
DANN	Benign	0.96
DEOGEN2	Benign	0.091	T
Eigen	Benign	-0.77
Eigen_PC	Benign	-0.96
FATHMM_MKL	Benign	0.0015	N
LIST_S2	Benign	0.26	T
MetaRNN	Benign	0.0016	T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	P;P;P
PROVEAN	Benign	-0.99	N
REVEL	Benign	0.012
Sift	Pathogenic	0.0	D
Vest4		0.19
MVP		0.068
ClinPred		0.020	T
GERP RS		0.82

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: rs79030053; hg19: chr7-81679904;