ENST00000423588.1:c.920A>T

Variant names:

• chr7-82050588-T-A
• rs79030053
• ENST00000423588.1:c.920A>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000423588.1(CACNA2D1):​c.920A>T​(p.Asn307Ile) variant causes a missense 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. 13/16 in silico tools predict 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 ENST00000423588.1 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.456
• 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
• 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

  Inheritance: Unknown, AD Classification: LIMITED, NO_KNOWN Submitted by: Genomics England PanelApp, Ambry Genetics
• Brugada syndrome 1

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 446965.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.107 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000423588.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CACNA2D1	NM_000722.4	MANE Select	c.879+9840A>T		intron	N/A	NP_000713.2	P54289-2
	CACNA2D1	NM_001302890.2		c.920A>T	p.Asn307Ile	missense	Exon 11 of 11	NP_001289819.1	E7ERK3
	CACNA2D1	NM_001366867.1		c.879+9840A>T		intron	N/A	NP_001353796.1	P54289-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CACNA2D1	ENST00000423588.1	TSL:1	c.920A>T	p.Asn307Ile	missense	Exon 11 of 11	ENSP00000405395.1	E7ERK3
	CACNA2D1	ENST00000356860.8	TSL:1 MANE Select	c.879+9840A>T		intron	N/A	ENSP00000349320.3	P54289-2
	CACNA2D1	ENST00000443883.2	TSL:5	c.879+9840A>T		intron	N/A	ENSP00000409374.2	H0Y715

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

GnomAD2 exomes AF: 0.00672 AC: 919 AN: 136814 AF XY: 0.00516

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 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

African (AFR) AF: 0.108 AC: 1702 AN: 15802

American (AMR) AF: 0.00691 AC: 240 AN: 34714

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 20026

East Asian (EAS) AF: 0.00 AC: 0 AN: 32094

South Asian (SAS) AF: 0.000159 AC: 10 AN: 62774

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33562

Middle Eastern (MID) AF: 0.00319 AC: 13 AN: 4074

European-Non Finnish (NFE) AF: 0.000347 AC: 110 AN: 316840

Other (OTH) AF: 0.00970 AC: 297 AN: 30614

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

African (AFR) AF: 0.110 AC: 4547 AN: 41500

American (AMR) AF: 0.0122 AC: 186 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.000456 AC: 31 AN: 68040

Other (OTH) AF: 0.0227 AC: 48 AN: 2114

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

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.085
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
PhyloP100		-0.46
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
Mutation Taster		=98/2	polymorphism (auto)

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

Other links and lift over

dbSNP: rs79030053; hg19: chr7-81679904;