12-1878079-G-A

Variant names:

• chr12-1878079-G-A
• rs7308134
• NM_172364.5:c.1719+236C>T

Variant summary

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

The NM_172364.5(CACNA2D4):​c.1719+236C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.216 in 152,134 control chromosomes in the GnomAD database, including 5,971 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 0.22 (5971 hom., cov: 33)
• Consequence: CACNA2D4 NM_172364.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.207
• 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):

• 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=-0.9).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.495 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.1719+236C>T		intron	N/A	NP_758952.4

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CACNA2D4	ENST00000382722.10	TSL:1 MANE Select	c.1719+236C>T		intron	N/A	ENSP00000372169.4
	CACNA2D4	ENST00000586184.5	TSL:5	c.1719+236C>T		intron	N/A	ENSP00000465060.1
	CACNA2D4	ENST00000587995.5	TSL:5	c.1644+877C>T		intron	N/A	ENSP00000465372.1

Frequencies

GnomAD3 genomes AF: 0.216 AC: 32835 AN: 152016 Hom.: 5943 Cov.: 33

Gnomad AFR AF: 0.500

Gnomad AMI AF: 0.0625

Gnomad AMR AF: 0.111

Gnomad ASJ AF: 0.130

Gnomad EAS AF: 0.0368

Gnomad SAS AF: 0.169

Gnomad FIN AF: 0.0781

Gnomad MID AF: 0.127

Gnomad NFE AF: 0.113

Gnomad OTH AF: 0.170

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

GnomAD4 genome AF: 0.216 AC: 32913 AN: 152134 Hom.: 5971 Cov.: 33 AF XY: 0.211 AC XY: 15665 AN XY: 74394

African (AFR) AF: 0.501 AC: 20757 AN: 41458

American (AMR) AF: 0.111 AC: 1695 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.130 AC: 452 AN: 3470

East Asian (EAS) AF: 0.0369 AC: 191 AN: 5178

South Asian (SAS) AF: 0.169 AC: 817 AN: 4826

European-Finnish (FIN) AF: 0.0781 AC: 827 AN: 10584

Middle Eastern (MID) AF: 0.126 AC: 37 AN: 294

European-Non Finnish (NFE) AF: 0.113 AC: 7717 AN: 67998

Other (OTH) AF: 0.172 AC: 363 AN: 2116

Alfa AF: 0.151 Hom.: 8221

Bravo AF: 0.227

Asia WGS AF: 0.166 AC: 577 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	1.8
DANN	Benign	0.68
PhyloP100		-0.21
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: rs7308134; hg19: chr12-1987245;