rs33912216

Variant names:

• chr12-1793739-G-A
• rs33912216
• NM_172364.5:c.3330C>T

Your query was ambiguous. Multiple possible variants found:

• chr12-1793739-G-A
• chr12-1793739-G-C

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.3330C>T​(p.Gly1110Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0968 in 1,612,800 control chromosomes in the GnomAD database, including 8,584 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.11 (991 hom., cov: 33)
  • Exomes 𝑓: 0.096 (7593 hom.)
• Consequence: CACNA2D4 NM_172364.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -5.38
• Publications: 9 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=-0.87).
• BP6: Variant 12-1793739-G-A is Benign according to our data. Variant chr12-1793739-G-A is described in ClinVar as Benign. ClinVar VariationId is 197051.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-5.38 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.183 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.3330C>T	p.Gly1110Gly	synonymous	Exon 38 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.3330C>T	p.Gly1110Gly	synonymous	Exon 38 of 38	ENSP00000372169.4	Q7Z3S7-1
	CACNA2D4	ENST00000587995.5	TSL:5	c.3255C>T	p.Gly1085Gly	synonymous	Exon 37 of 37	ENSP00000465372.1	K7EJY1
	CACNA2D4	ENST00000588077.5	TSL:5	c.3138C>T	p.Gly1046Gly	synonymous	Exon 38 of 38	ENSP00000468530.1	Q7Z3S7-4

Frequencies

GnomAD3 genomes AF: 0.107 AC: 16322 AN: 152152 Hom.: 992 Cov.: 33

Gnomad AFR AF: 0.120

Gnomad AMI AF: 0.105

Gnomad AMR AF: 0.189

Gnomad ASJ AF: 0.0689

Gnomad EAS AF: 0.0648

Gnomad SAS AF: 0.119

Gnomad FIN AF: 0.111

Gnomad MID AF: 0.0759

Gnomad NFE AF: 0.0851

Gnomad OTH AF: 0.115

GnomAD2 exomes AF: 0.114 AC: 28140 AN: 245934 AF XY: 0.111

Gnomad AFR exome AF: 0.126

Gnomad AMR exome AF: 0.232

Gnomad ASJ exome AF: 0.0767

Gnomad EAS exome AF: 0.0537

Gnomad FIN exome AF: 0.111

Gnomad NFE exome AF: 0.0862

Gnomad OTH exome AF: 0.112

GnomAD4 exome AF: 0.0957 AC: 139733 AN: 1460530 Hom.: 7593 Cov.: 32 AF XY: 0.0956 AC XY: 69486 AN XY: 726606

African (AFR) AF: 0.122 AC: 4088 AN: 33470

American (AMR) AF: 0.228 AC: 10196 AN: 44680

Ashkenazi Jewish (ASJ) AF: 0.0757 AC: 1976 AN: 26114

East Asian (EAS) AF: 0.0528 AC: 2095 AN: 39696

South Asian (SAS) AF: 0.130 AC: 11234 AN: 86224

European-Finnish (FIN) AF: 0.111 AC: 5860 AN: 52790

Middle Eastern (MID) AF: 0.104 AC: 587 AN: 5664

European-Non Finnish (NFE) AF: 0.0880 AC: 97842 AN: 1111558

Other (OTH) AF: 0.0970 AC: 5855 AN: 60334

GnomAD4 genome AF: 0.107 AC: 16334 AN: 152270 Hom.: 991 Cov.: 33 AF XY: 0.109 AC XY: 8149 AN XY: 74454

African (AFR) AF: 0.120 AC: 4973 AN: 41538

American (AMR) AF: 0.189 AC: 2886 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.0689 AC: 239 AN: 3468

East Asian (EAS) AF: 0.0638 AC: 330 AN: 5176

South Asian (SAS) AF: 0.119 AC: 576 AN: 4828

European-Finnish (FIN) AF: 0.111 AC: 1183 AN: 10614

Middle Eastern (MID) AF: 0.0714 AC: 21 AN: 294

European-Non Finnish (NFE) AF: 0.0851 AC: 5789 AN: 68018

Other (OTH) AF: 0.114 AC: 241 AN: 2112

Alfa AF: 0.100 Hom.: 682

Bravo AF: 0.115

Asia WGS AF: 0.102 AC: 356 AN: 3478

EpiCase AF: 0.0842

EpiControl AF: 0.0893

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.030
DANN	Benign	0.73
PhyloP100		-5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs33912216; hg19: chr12-1902905; COSMIC: COSV54959742; COSMIC: COSV54959742;