12-1839781-G-T

Variant names:

• chr12-1839781-G-T
• rs758166
• NM_172364.5:c.2551+958C>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_172364.5(CACNA2D4):​c.2551+958C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0707 in 151,898 control chromosomes in the GnomAD database, including 888 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.071 (888 hom., cov: 33)
• Consequence: CACNA2D4 NM_172364.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0340
• Publications: 1 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.381 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.2551+958C>A		intron	N/A	NP_758952.4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CACNA2D4	ENST00000382722.10	TSL:1 MANE Select	c.2551+958C>A		intron	N/A	ENSP00000372169.4	Q7Z3S7-1
	CACNA2D4	ENST00000586184.5	TSL:5	c.2551+958C>A		intron	N/A	ENSP00000465060.1	Q7Z3S7-5
	CACNA2D4	ENST00000587995.5	TSL:5	c.2476+958C>A		intron	N/A	ENSP00000465372.1	K7EJY1

Frequencies

GnomAD3 genomes AF: 0.0706 AC: 10721 AN: 151780 Hom.: 882 Cov.: 33

Gnomad AFR AF: 0.0950

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.116

Gnomad ASJ AF: 0.0361

Gnomad EAS AF: 0.394

Gnomad SAS AF: 0.226

Gnomad FIN AF: 0.0443

Gnomad MID AF: 0.0570

Gnomad NFE AF: 0.0170

Gnomad OTH AF: 0.0688

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.0707 AC: 10736 AN: 151898 Hom.: 888 Cov.: 33 AF XY: 0.0782 AC XY: 5802 AN XY: 74238

African (AFR) AF: 0.0949 AC: 3941 AN: 41512

American (AMR) AF: 0.116 AC: 1754 AN: 15162

Ashkenazi Jewish (ASJ) AF: 0.0361 AC: 121 AN: 3350

East Asian (EAS) AF: 0.395 AC: 2034 AN: 5152

South Asian (SAS) AF: 0.225 AC: 1084 AN: 4820

European-Finnish (FIN) AF: 0.0443 AC: 470 AN: 10614

Middle Eastern (MID) AF: 0.0510 AC: 15 AN: 294

European-Non Finnish (NFE) AF: 0.0170 AC: 1156 AN: 67982

Other (OTH) AF: 0.0767 AC: 161 AN: 2100

Alfa AF: 0.0278 Hom.: 29

Bravo AF: 0.0752

Asia WGS AF: 0.317 AC: 1100 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.44
DANN	Benign	0.55
PhyloP100		0.034
Mutation Taster		=100/0	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: rs758166; hg19: chr12-1948947;