12-1840773-C-T

Variant names:

• chr12-1840773-C-T
• rs33972365
• NM_172364.5:c.2517G>A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_172364.5(CACNA2D4):​c.2517G>A​(p.Ala839Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.106 in 1,613,590 control chromosomes in the GnomAD database, including 10,238 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.14 (1798 hom., cov: 34)
  • Exomes 𝑓: 0.10 (8440 hom.)
• Consequence: CACNA2D4 NM_172364.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4 O:1
• Conservation: PhyloP100: -2.06
• Publications: 6 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: AR, Unknown Classification: STRONG, MODERATE, LIMITED Submitted by: Laboratory for Molecular Medicine, G2P, Labcorp Genetics (formerly Invitae)
• cone-rod dystrophy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.54).
• BP6: Variant 12-1840773-C-T is Benign according to our data. Variant chr12-1840773-C-T is described in ClinVar as Benign. ClinVar VariationId is 100607.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.06 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.234 is higher than 0.05.

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.2517G>A	p.Ala839Ala	synonymous	Exon 26 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.2517G>A	p.Ala839Ala	synonymous	Exon 26 of 38	ENSP00000372169.4	Q7Z3S7-1
	CACNA2D4	ENST00000586184.5	TSL:5	c.2517G>A	p.Ala839Ala	synonymous	Exon 26 of 37	ENSP00000465060.1	Q7Z3S7-5
	CACNA2D4	ENST00000587995.5	TSL:5	c.2442G>A	p.Ala814Ala	synonymous	Exon 25 of 37	ENSP00000465372.1	K7EJY1

Frequencies

GnomAD3 genomes AF: 0.136 AC: 20652 AN: 152100 Hom.: 1794 Cov.: 34

Gnomad AFR AF: 0.238

Gnomad AMI AF: 0.0724

Gnomad AMR AF: 0.0875

Gnomad ASJ AF: 0.0942

Gnomad EAS AF: 0.0146

Gnomad SAS AF: 0.104

Gnomad FIN AF: 0.105

Gnomad MID AF: 0.0728

Gnomad NFE AF: 0.105

Gnomad OTH AF: 0.106

GnomAD2 exomes AF: 0.104 AC: 25861 AN: 249110 AF XY: 0.102

Gnomad AFR exome AF: 0.241

Gnomad AMR exome AF: 0.0896

Gnomad ASJ exome AF: 0.0916

Gnomad EAS exome AF: 0.0141

Gnomad FIN exome AF: 0.107

Gnomad NFE exome AF: 0.103

Gnomad OTH exome AF: 0.101

GnomAD4 exome AF: 0.103 AC: 149916 AN: 1461372 Hom.: 8440 Cov.: 31 AF XY: 0.102 AC XY: 74021 AN XY: 726972

African (AFR) AF: 0.235 AC: 7880 AN: 33472

American (AMR) AF: 0.0892 AC: 3987 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0946 AC: 2470 AN: 26120

East Asian (EAS) AF: 0.0131 AC: 519 AN: 39700

South Asian (SAS) AF: 0.103 AC: 8914 AN: 86256

European-Finnish (FIN) AF: 0.107 AC: 5705 AN: 53280

Middle Eastern (MID) AF: 0.0758 AC: 437 AN: 5768

European-Non Finnish (NFE) AF: 0.102 AC: 113692 AN: 1111688

Other (OTH) AF: 0.105 AC: 6312 AN: 60366

GnomAD4 genome AF: 0.136 AC: 20696 AN: 152218 Hom.: 1798 Cov.: 34 AF XY: 0.133 AC XY: 9889 AN XY: 74430

African (AFR) AF: 0.238 AC: 9889 AN: 41500

American (AMR) AF: 0.0873 AC: 1336 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.0942 AC: 327 AN: 3470

East Asian (EAS) AF: 0.0149 AC: 77 AN: 5184

South Asian (SAS) AF: 0.104 AC: 501 AN: 4830

European-Finnish (FIN) AF: 0.105 AC: 1109 AN: 10608

Middle Eastern (MID) AF: 0.0680 AC: 20 AN: 294

European-Non Finnish (NFE) AF: 0.105 AC: 7138 AN: 68008

Other (OTH) AF: 0.110 AC: 233 AN: 2116

Alfa AF: 0.117 Hom.: 573

Bravo AF: 0.137

Asia WGS AF: 0.0920 AC: 318 AN: 3478

EpiCase AF: 0.0955

EpiControl AF: 0.0971

ClinVar

ClinVar submissions as Germline

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
BayesDel_noAF	Benign	-0.54
CADD	Benign	0.54
DANN	Benign	0.87
PhyloP100		-2.1
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs33972365; hg19: chr12-1949939; COSMIC: COSV54565241; COSMIC: COSV54565241;