rs62621429

Positions:

• chr12-1801620-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_172364.5(CACNA2D4):​c.2746G>A​(p.Asp916Asn) variant causes a missense change. The variant allele was found at a frequency of 0.0265 in 1,587,446 control chromosomes in the GnomAD database, including 726 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.021 (43 hom., cov: 32)
  • Exomes 𝑓: 0.027 (683 hom.)
• Consequence: CACNA2D4 NM_172364.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 5.30

Genes affected

CACNA2D4 (HGNC:20202): (calcium voltage-gated channel auxiliary subunit alpha2delta 4) This gene encodes a member of the alpha-2/delta subunit family, a protein in the voltage-dependent calcium channel complex. Calcium channels mediate the influx of calcium ions into the cell upon membrane polarization and consist of a complex of alpha-1, alpha-2/delta, beta, and gamma subunits in a 1:1:1:1 ratio. Various versions of each of these subunits exist, either expressed from similar genes or the result of alternative splicing. Research on a highly similar protein in rabbit suggests the protein described in this record is cleaved into alpha-2 and delta subunits. Alternate transcriptional splice variants of this gene have been observed but have not been thoroughly characterized. [provided by RefSeq, Jul 2008]

CACNA2D4 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.010107875).
• BP6: Variant 12-1801620-C-T is Benign according to our data. Variant chr12-1801620-C-T is described in ClinVar as [Benign]. Clinvar id is 262816.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-1801620-C-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0214 (3258/152298) while in subpopulation NFE AF= 0.0303 (2059/68022). AF 95% confidence interval is 0.0292. There are 43 homozygotes in gnomad4. There are 1583 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 43 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA2D4	NM_172364.5	c.2746G>A	p.Asp916Asn	missense_variant	30/38	ENST00000382722.10	NP_758952.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA2D4	ENST00000382722.10	c.2746G>A	p.Asp916Asn	missense_variant	30/38	1	NM_172364.5	ENSP00000372169.4
CACNA2D4	ENST00000586184.5	c.2746G>A	p.Asp916Asn	missense_variant	30/37	5		ENSP00000465060.1
CACNA2D4	ENST00000587995.5	c.2671G>A	p.Asp891Asn	missense_variant	29/37	5		ENSP00000465372.1
CACNA2D4	ENST00000585708.5	c.2554G>A	p.Asp852Asn	missense_variant	30/37	5		ENSP00000467697.1
CACNA2D4	ENST00000588077.5	c.2554G>A	p.Asp852Asn	missense_variant	30/38	5		ENSP00000468530.1
CACNA2D4	ENST00000536846.6	c.190G>A	p.Asp64Asn	missense_variant	4/12	5		ENSP00000468167.1
CACNA2D4	ENST00000538027.6	c.181G>A	p.Asp61Asn	missense_variant	4/12	5		ENSP00000443038.2
CACNA2D4	ENST00000538450.5	c.136G>A	p.Asp46Asn	missense_variant	3/11	2		ENSP00000446341.1
CACNA2D4	ENST00000444595.6	n.*930G>A		non_coding_transcript_exon_variant	29/37	1		ENSP00000403371.2
CACNA2D4	ENST00000444595.6	n.*930G>A		3_prime_UTR_variant	29/37	1		ENSP00000403371.2
CACNA2D4	ENST00000537784.5	n.562-502G>A		intron_variant		1		ENSP00000440231.2
CACNA2D4	ENST00000545595.6	n.112-502G>A		intron_variant		1		ENSP00000442329.2
CACNA2D4	ENST00000585385.5	n.157-502G>A		intron_variant		5		ENSP00000467333.1

Frequencies

GnomAD3 genomes AF: 0.0214 AC: 3260 AN: 152180 Hom.: 43 Cov.: 32

Gnomad AFR AF: 0.00560

Gnomad AMI AF: 0.0186

Gnomad AMR AF: 0.0228

Gnomad ASJ AF: 0.0602

Gnomad EAS AF: 0.000577

Gnomad SAS AF: 0.0143

Gnomad FIN AF: 0.0225

Gnomad MID AF: 0.0791

Gnomad NFE AF: 0.0303

Gnomad OTH AF: 0.0277

GnomAD3 exomes AF: 0.0225 AC: 4709 AN: 208914 Hom.: 82 AF XY: 0.0232 AC XY: 2613 AN XY: 112590

Gnomad AFR exome AF: 0.00501

Gnomad AMR exome AF: 0.0165

Gnomad ASJ exome AF: 0.0551

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0149

Gnomad FIN exome AF: 0.0187

Gnomad NFE exome AF: 0.0299

Gnomad OTH exome AF: 0.0282

GnomAD4 exome AF: 0.0271 AC: 38839 AN: 1435148 Hom.: 683 Cov.: 30 AF XY: 0.0267 AC XY: 18967 AN XY: 711402

Gnomad4 AFR exome AF: 0.00463

Gnomad4 AMR exome AF: 0.0169

Gnomad4 ASJ exome AF: 0.0565

Gnomad4 EAS exome AF: 0.0000521

Gnomad4 SAS exome AF: 0.0147

Gnomad4 FIN exome AF: 0.0203

Gnomad4 NFE exome AF: 0.0295

Gnomad4 OTH exome AF: 0.0291

GnomAD4 genome AF: 0.0214 AC: 3258 AN: 152298 Hom.: 43 Cov.: 32 AF XY: 0.0213 AC XY: 1583 AN XY: 74472

Gnomad4 AFR AF: 0.00558

Gnomad4 AMR AF: 0.0228

Gnomad4 ASJ AF: 0.0602

Gnomad4 EAS AF: 0.000578

Gnomad4 SAS AF: 0.0141

Gnomad4 FIN AF: 0.0225

Gnomad4 NFE AF: 0.0303

Gnomad4 OTH AF: 0.0279

Alfa AF: 0.0295 Hom.: 113

Bravo AF: 0.0203

TwinsUK AF: 0.0302 AC: 112

ALSPAC AF: 0.0314 AC: 121

ESP6500AA AF: 0.00517 AC: 21

ESP6500EA AF: 0.0265 AC: 221

ExAC AF: 0.0189 AC: 2280

Asia WGS AF: 0.00837 AC: 29 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Retinal cone dystrophy 4 Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 14, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.28
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.068	T;.;.;.;.;.;.
Eigen	Uncertain	0.44
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Uncertain	0.97	D
MetaRNN	Benign	0.010	T;T;T;T;T;T;T
MetaSVM	Uncertain	-0.27	T
MutationAssessor	Uncertain	2.4	M;.;.;.;.;M;.
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-2.3	N;N;.;.;.;.;.
REVEL	Uncertain	0.45
Sift	Benign	0.49	T;D;.;.;.;.;.
Sift4G	Uncertain	0.036	D;T;D;D;T;D;D
Polyphen		0.96	D;D;.;P;.;.;.
Vest4		0.62
MPC		0.16
ClinPred		0.033	T
GERP RS		4.7
Varity_R		0.12
gMVP		0.88

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs62621429; hg19: chr12-1910786;