12-1916038-A-G

Variant names:

• chr12-1916038-A-G
• rs758158
• NM_172364.5:c.228-1103T>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.228-1103T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.935 in 152,232 control chromosomes in the GnomAD database, including 66,697 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 0.94 (66697 hom., cov: 31)
• Consequence: CACNA2D4 NM_172364.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0510
• Publications: 4 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.977 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA2D4	NM_172364.5	c.228-1103T>C		intron_variant	Intron 1 of 37	ENST00000382722.10	NP_758952.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA2D4	ENST00000382722.10	c.228-1103T>C		intron_variant	Intron 1 of 37	1	NM_172364.5	ENSP00000372169.4
CACNA2D4	ENST00000586184.5	c.228-1103T>C		intron_variant	Intron 1 of 36	5		ENSP00000465060.1
CACNA2D4	ENST00000587995.5	c.228-1103T>C		intron_variant	Intron 1 of 36	5		ENSP00000465372.1
CACNA2D4	ENST00000444595.6	n.228-1103T>C		intron_variant	Intron 1 of 36	1		ENSP00000403371.2

Frequencies

GnomAD3 genomes AF: 0.935 AC: 142255 AN: 152114 Hom.: 66635 Cov.: 31

Gnomad AFR AF: 0.983

Gnomad AMI AF: 0.865

Gnomad AMR AF: 0.913

Gnomad ASJ AF: 0.909

Gnomad EAS AF: 0.999

Gnomad SAS AF: 0.916

Gnomad FIN AF: 0.918

Gnomad MID AF: 0.886

Gnomad NFE AF: 0.913

Gnomad OTH AF: 0.916

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

GnomAD4 genome AF: 0.935 AC: 142376 AN: 152232 Hom.: 66697 Cov.: 31 AF XY: 0.934 AC XY: 69532 AN XY: 74432

African (AFR) AF: 0.983 AC: 40827 AN: 41532

American (AMR) AF: 0.912 AC: 13961 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.909 AC: 3156 AN: 3472

East Asian (EAS) AF: 0.999 AC: 5163 AN: 5166

South Asian (SAS) AF: 0.917 AC: 4427 AN: 4828

European-Finnish (FIN) AF: 0.918 AC: 9743 AN: 10608

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

European-Non Finnish (NFE) AF: 0.913 AC: 62108 AN: 68002

Other (OTH) AF: 0.917 AC: 1941 AN: 2116

Alfa AF: 0.913 Hom.: 102453

Bravo AF: 0.937

Asia WGS AF: 0.964 AC: 3355 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	1.8
DANN	Benign	0.52
PhyloP100		0.051
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: rs758158; hg19: chr12-2025204;