rs73038195

Variant names:

• chr12-1914926-T-C
• rs73038195
• NM_172364.5:c.237A>G

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.237A>G​(p.Leu79Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0908 in 1,610,796 control chromosomes in the GnomAD database, including 7,507 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.069 (555 hom., cov: 32)
  • Exomes 𝑓: 0.093 (6952 hom.)
• Consequence: CACNA2D4 NM_172364.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.462
• 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):

• inherited retinal dystrophy

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

  Inheritance: AR, Unknown Classification: STRONG, MODERATE, LIMITED Submitted by: Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), G2P
• 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=-0.56).
• BP6: Variant 12-1914926-T-C is Benign according to our data. Variant chr12-1914926-T-C is described in ClinVar as Benign. ClinVar VariationId is 262815.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.462 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.101 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CACNA2D4	NM_172364.5	MANE Select	c.237A>G	p.Leu79Leu	synonymous	Exon 2 of 38	NP_758952.4

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CACNA2D4	ENST00000382722.10	TSL:1 MANE Select	c.237A>G	p.Leu79Leu	synonymous	Exon 2 of 38	ENSP00000372169.4
	CACNA2D4	ENST00000586184.5	TSL:5	c.237A>G	p.Leu79Leu	synonymous	Exon 2 of 37	ENSP00000465060.1
	CACNA2D4	ENST00000587995.5	TSL:5	c.237A>G	p.Leu79Leu	synonymous	Exon 2 of 37	ENSP00000465372.1

Frequencies

GnomAD3 genomes AF: 0.0693 AC: 10529 AN: 151974 Hom.: 555 Cov.: 32

Gnomad AFR AF: 0.0214

Gnomad AMI AF: 0.0484

Gnomad AMR AF: 0.0512

Gnomad ASJ AF: 0.110

Gnomad EAS AF: 0.00154

Gnomad SAS AF: 0.0794

Gnomad FIN AF: 0.0800

Gnomad MID AF: 0.0696

Gnomad NFE AF: 0.103

Gnomad OTH AF: 0.0676

GnomAD2 exomes AF: 0.0782 AC: 19482 AN: 249214 AF XY: 0.0814

Gnomad AFR exome AF: 0.0167

Gnomad AMR exome AF: 0.0397

Gnomad ASJ exome AF: 0.113

Gnomad EAS exome AF: 0.000389

Gnomad FIN exome AF: 0.0881

Gnomad NFE exome AF: 0.102

Gnomad OTH exome AF: 0.0899

GnomAD4 exome AF: 0.0930 AC: 135666 AN: 1458704 Hom.: 6952 Cov.: 30 AF XY: 0.0932 AC XY: 67643 AN XY: 725842

African (AFR) AF: 0.0161 AC: 538 AN: 33454

American (AMR) AF: 0.0412 AC: 1841 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.112 AC: 2927 AN: 26126

East Asian (EAS) AF: 0.000227 AC: 9 AN: 39690

South Asian (SAS) AF: 0.0854 AC: 7366 AN: 86210

European-Finnish (FIN) AF: 0.0882 AC: 4709 AN: 53402

Middle Eastern (MID) AF: 0.0923 AC: 532 AN: 5766

European-Non Finnish (NFE) AF: 0.101 AC: 112357 AN: 1109062

Other (OTH) AF: 0.0894 AC: 5387 AN: 60270

GnomAD4 genome AF: 0.0692 AC: 10527 AN: 152092 Hom.: 555 Cov.: 32 AF XY: 0.0666 AC XY: 4952 AN XY: 74334

African (AFR) AF: 0.0214 AC: 886 AN: 41482

American (AMR) AF: 0.0510 AC: 780 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.110 AC: 382 AN: 3470

East Asian (EAS) AF: 0.00135 AC: 7 AN: 5168

South Asian (SAS) AF: 0.0798 AC: 384 AN: 4810

European-Finnish (FIN) AF: 0.0800 AC: 846 AN: 10574

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

European-Non Finnish (NFE) AF: 0.104 AC: 7038 AN: 67992

Other (OTH) AF: 0.0664 AC: 140 AN: 2108

Alfa AF: 0.0918 Hom.: 393

Bravo AF: 0.0620

Asia WGS AF: 0.0340 AC: 119 AN: 3478

EpiCase AF: 0.0986

EpiControl AF: 0.102

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.56
CADD	Benign	5.6
DANN	Benign	0.65
PhyloP100		-0.46
PromoterAI		0.011	Neutral
Mutation Taster		=98/2	polymorphism (auto)

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: rs73038195; hg19: chr12-2024092; COSMIC: COSV108096282; COSMIC: COSV108096282;