ENST00000423588.1:c.920A>G

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The ENST00000423588.1(CACNA2D1):​c.920A>G​(p.Asn307Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000727 in 550,506 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/17 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N307I) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000073 (0 hom.)
• Consequence: CACNA2D1 ENST00000423588.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.456
• Publications: 0 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.07200423).

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>G		intron	N/A	NP_000713.2	P54289-2
	CACNA2D1	NM_001302890.2		c.920A>G	p.Asn307Ser	missense	Exon 11 of 11	NP_001289819.1	E7ERK3
	CACNA2D1	NM_001366867.1		c.879+9840A>G		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>G	p.Asn307Ser	missense	Exon 11 of 11	ENSP00000405395.1	E7ERK3
	CACNA2D1	ENST00000356860.8	TSL:1 MANE Select	c.879+9840A>G		intron	N/A	ENSP00000349320.3	P54289-2
	CACNA2D1	ENST00000443883.2	TSL:5	c.879+9840A>G		intron	N/A	ENSP00000409374.2	H0Y715

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000727 AC: 4 AN: 550506 Hom.: 0 Cov.: 0 AF XY: 0.0000101 AC XY: 3 AN XY: 298028

African (AFR) AF: 0.00 AC: 0 AN: 15806

American (AMR) AF: 0.0000576 AC: 2 AN: 34716

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

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 62774

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

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4074

European-Non Finnish (NFE) AF: 0.00000316 AC: 1 AN: 316840

Other (OTH) AF: 0.0000327 AC: 1 AN: 30614

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.063
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	0.18
DANN	Benign	0.80
DEOGEN2	Benign	0.019	T
Eigen	Benign	-0.79
Eigen_PC	Benign	-0.97
FATHMM_MKL	Benign	0.0078	N
LIST_S2	Benign	0.35	T
M_CAP	Benign	0.00075	T
MetaRNN	Benign	0.072	T
MetaSVM	Benign	-1.0	T
PhyloP100		-0.46
PROVEAN	Benign	-0.66	N
REVEL	Benign	0.022
Sift	Pathogenic	0.0	D
Vest4		0.074
MutPred		0.21		Gain of phosphorylation at N307 (P = 0.0042)
MVP		0.12
ClinPred		0.099	T
GERP RS		0.82
Mutation Taster		=100/0	polymorphism

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;