rs76224631

Variant names:

• chr12-1856099-T-C
• rs76224631
• NM_172364.5:c.2065A>G

Variant summary

Our verdict is Benign. The variant received -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. 15/21 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
• Publications: 5 publications found

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 Gene-Disease associations (from GenCC):

• CACNA2D4-related retinopathy

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• retinal cone dystrophy 4

  Inheritance: Unknown, AR Classification: STRONG, MODERATE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), G2P, Laboratory for Molecular Medicine
• cone-rod dystrophy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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 the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 69 AD,Unknown,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_172364.5. 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
	CACNA2D4	NM_172364.5	MANE Select	c.2065A>G	p.Ile689Val	missense	Exon 22 of 38	NP_758952.4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CACNA2D4	ENST00000382722.10	TSL:1 MANE Select	c.2065A>G	p.Ile689Val	missense	Exon 22 of 38	ENSP00000372169.4	Q7Z3S7-1
	CACNA2D4	ENST00000586184.5	TSL:5	c.2065A>G	p.Ile689Val	missense	Exon 22 of 37	ENSP00000465060.1	Q7Z3S7-5
	CACNA2D4	ENST00000587995.5	TSL:5	c.1990A>G	p.Ile664Val	missense	Exon 21 of 37	ENSP00000465372.1	K7EJY1

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

GnomAD2 exomes AF: 0.00379 AC: 944 AN: 249262 AF XY: 0.00298

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 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

African (AFR) AF: 0.0454 AC: 1519 AN: 33472

American (AMR) AF: 0.00445 AC: 199 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26124

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.0000812 AC: 7 AN: 86256

European-Finnish (FIN) AF: 0.0000375 AC: 2 AN: 53400

Middle Eastern (MID) AF: 0.00659 AC: 38 AN: 5768

European-Non Finnish (NFE) AF: 0.000495 AC: 550 AN: 1111816

Other (OTH) AF: 0.00459 AC: 277 AN: 60366

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

African (AFR) AF: 0.0479 AC: 1990 AN: 41586

American (AMR) AF: 0.00908 AC: 139 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.000588 AC: 40 AN: 68036

Other (OTH) AF: 0.0114 AC: 24 AN: 2114

Alfa AF: 0.00788 Hom.: 12

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

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (3)
-	-	1	not specified (1)
-	-	1	Retinal cone dystrophy 4 (1)

Computational scores

Source: dbNSFP v4.9

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
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.3	L
PhyloP100		-0.61
PrimateAI	Benign	0.28	T
PROVEAN	Benign	0.26	N
REVEL	Benign	0.020
Sift	Benign	0.78	T
Sift4G	Benign	0.82	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
Mutation Taster		=98/2	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: rs76224631; hg19: chr12-1965265; COSMIC: COSV99028010; COSMIC: COSV99028010;