rs76224631

Positions:

• chr12-1856099-T-C

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.2065A>G​(p.Ile689Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00297 in 1,613,976 control chromosomes in the GnomAD database, including 111 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.014 (69 hom., cov: 33)
  • Exomes 𝑓: 0.0018 (42 hom.)
• Consequence: CACNA2D4 NM_172364.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4 O:1
• Conservation: PhyloP100: -0.615

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=0.0025875866).
• BP6: Variant 12-1856099-T-C is Benign according to our data. Variant chr12-1856099-T-C is described in ClinVar as [Benign]. Clinvar id is 100606.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0144 (2197/152350) while in subpopulation AFR AF= 0.0479 (1990/41586). AF 95% confidence interval is 0.0461. There are 69 homozygotes in gnomad4. There are 1056 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 69 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA2D4	NM_172364.5	c.2065A>G	p.Ile689Val	missense_variant	22/38	ENST00000382722.10	NP_758952.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA2D4	ENST00000382722.10	c.2065A>G	p.Ile689Val	missense_variant	22/38	1	NM_172364.5	ENSP00000372169.4
CACNA2D4	ENST00000586184.5	c.2065A>G	p.Ile689Val	missense_variant	22/37	5		ENSP00000465060.1
CACNA2D4	ENST00000587995.5	c.1990A>G	p.Ile664Val	missense_variant	21/37	5		ENSP00000465372.1
CACNA2D4	ENST00000585708.5	c.1873A>G	p.Ile625Val	missense_variant	22/37	5		ENSP00000467697.1
CACNA2D4	ENST00000588077.5	c.1873A>G	p.Ile625Val	missense_variant	22/38	5		ENSP00000468530.1
CACNA2D4	ENST00000444595.6	n.*311A>G		non_coding_transcript_exon_variant	22/37	1		ENSP00000403371.2
CACNA2D4	ENST00000444595.6	n.*311A>G		3_prime_UTR_variant	22/37	1		ENSP00000403371.2

Frequencies

GnomAD3 genomes AF: 0.0144 AC: 2193 AN: 152232 Hom.: 69 Cov.: 33

Gnomad AFR AF: 0.0479

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00910

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.000588

Gnomad OTH AF: 0.0115

GnomAD3 exomes AF: 0.00379 AC: 944 AN: 249262 Hom.: 24 AF XY: 0.00298 AC XY: 403 AN XY: 135220

Gnomad AFR exome AF: 0.0453

Gnomad AMR exome AF: 0.00440

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000654

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000655

Gnomad OTH exome AF: 0.00248

GnomAD4 exome AF: 0.00177 AC: 2593 AN: 1461626 Hom.: 42 Cov.: 32 AF XY: 0.00162 AC XY: 1180 AN XY: 727090

Gnomad4 AFR exome AF: 0.0454

Gnomad4 AMR exome AF: 0.00445

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000812

Gnomad4 FIN exome AF: 0.0000375

Gnomad4 NFE exome AF: 0.000495

Gnomad4 OTH exome AF: 0.00459

GnomAD4 genome AF: 0.0144 AC: 2197 AN: 152350 Hom.: 69 Cov.: 33 AF XY: 0.0142 AC XY: 1056 AN XY: 74512

Gnomad4 AFR AF: 0.0479

Gnomad4 AMR AF: 0.00908

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000588

Gnomad4 OTH AF: 0.0114

Alfa AF: 0.00718 Hom.: 6

Bravo AF: 0.0158

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.0377 AC: 152

ESP6500EA AF: 0.000120 AC: 1

ExAC AF: 0.00434 AC: 525

Asia WGS AF: 0.00404 AC: 14 AN: 3478

EpiCase AF: 0.000872

EpiControl AF: 0.000830

ClinVar

Significance: Benign

Submissions summary: Benign:4 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2 Other:1

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -
not provided, no classification provided	literature only	NEI Ophthalmic Genomics Laboratory, National Institutes of Health	-	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Retinal cone dystrophy 4 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.064
BayesDel_addAF	Benign	-0.71	T
BayesDel_noAF	Benign	-0.75
CADD	Benign	0.016
DANN	Benign	0.90
DEOGEN2	Benign	0.021	T;.;.;.;.;.
Eigen	Benign	-0.84
Eigen_PC	Benign	-0.81
FATHMM_MKL	Benign	0.064	N
MetaRNN	Benign	0.0026	T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.3	L;.;.;L;.;.
PrimateAI	Benign	0.28	T
PROVEAN	Benign	0.26	N;.;.;.;.;.
REVEL	Benign	0.020
Sift	Benign	0.78	T;.;.;.;.;.
Sift4G	Benign	0.82	T;T;T;T;T;T
Polyphen		0.0010	B;.;.;.;.;.
Vest4		0.16
MVP		0.12
MPC		0.11
ClinPred		0.0033	T
GERP RS		-1.2
Varity_R		0.023
gMVP		0.43

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: rs76224631; hg19: chr12-1965265; COSMIC: COSV99028010; COSMIC: COSV99028010;