12-1854782-A-G

Variant names:

• chr12-1854782-A-G
• rs2041140
• NM_172364.5:c.2153-738T>C

Variant summary

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

The NM_172364.5(CACNA2D4):​c.2153-738T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.897 in 152,248 control chromosomes in the GnomAD database, including 61,319 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 0.90 (61319 hom., cov: 32)
• Consequence: CACNA2D4 NM_172364.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.987
• Publications: 7 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 = 0.977 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.2153-738T>C		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.2153-738T>C		intron	N/A	ENSP00000372169.4	Q7Z3S7-1
	CACNA2D4	ENST00000586184.5	TSL:5	c.2153-738T>C		intron	N/A	ENSP00000465060.1	Q7Z3S7-5
	CACNA2D4	ENST00000587995.5	TSL:5	c.2078-738T>C		intron	N/A	ENSP00000465372.1	K7EJY1

Frequencies

GnomAD3 genomes AF: 0.897 AC: 136405 AN: 152130 Hom.: 61268 Cov.: 32

Gnomad AFR AF: 0.892

Gnomad AMI AF: 0.934

Gnomad AMR AF: 0.914

Gnomad ASJ AF: 0.833

Gnomad EAS AF: 1.00

Gnomad SAS AF: 0.968

Gnomad FIN AF: 0.954

Gnomad MID AF: 0.892

Gnomad NFE AF: 0.876

Gnomad OTH AF: 0.894

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

GnomAD4 genome AF: 0.897 AC: 136515 AN: 152248 Hom.: 61319 Cov.: 32 AF XY: 0.903 AC XY: 67196 AN XY: 74438

African (AFR) AF: 0.892 AC: 37048 AN: 41522

American (AMR) AF: 0.914 AC: 13984 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.833 AC: 2890 AN: 3470

East Asian (EAS) AF: 1.00 AC: 5172 AN: 5174

South Asian (SAS) AF: 0.967 AC: 4667 AN: 4824

European-Finnish (FIN) AF: 0.954 AC: 10136 AN: 10620

Middle Eastern (MID) AF: 0.888 AC: 261 AN: 294

European-Non Finnish (NFE) AF: 0.876 AC: 59611 AN: 68020

Other (OTH) AF: 0.895 AC: 1894 AN: 2116

Alfa AF: 0.881 Hom.: 97282

Bravo AF: 0.892

Asia WGS AF: 0.975 AC: 3390 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	7.1
DANN	Benign	0.88
PhyloP100		0.99
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs2041140; hg19: chr12-1963948;