12-1912229-T-C

Variant names:

• chr12-1912229-T-C
• rs4765864
• NM_172364.5:c.426+794A>G

Variant summary

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

The NM_172364.5(CACNA2D4):​c.426+794A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.227 in 152,186 control chromosomes in the GnomAD database, including 4,130 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 0.23 (4130 hom., cov: 33)
• Consequence: CACNA2D4 NM_172364.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0400
• Publications: 3 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=-0.78).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.267 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA2D4	NM_172364.5	c.426+794A>G		intron_variant	Intron 3 of 37	ENST00000382722.10	NP_758952.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA2D4	ENST00000382722.10	c.426+794A>G		intron_variant	Intron 3 of 37	1	NM_172364.5	ENSP00000372169.4
CACNA2D4	ENST00000586184.5	c.426+794A>G		intron_variant	Intron 3 of 36	5		ENSP00000465060.1
CACNA2D4	ENST00000587995.5	c.426+794A>G		intron_variant	Intron 3 of 36	5		ENSP00000465372.1
CACNA2D4	ENST00000585708.5	c.234+794A>G		intron_variant	Intron 3 of 36	5		ENSP00000467697.1
CACNA2D4	ENST00000588077.5	c.234+794A>G		intron_variant	Intron 3 of 37	5		ENSP00000468530.1
CACNA2D4	ENST00000444595.6	n.426+794A>G		intron_variant	Intron 3 of 36	1		ENSP00000403371.2

Frequencies

GnomAD3 genomes AF: 0.227 AC: 34520 AN: 152068 Hom.: 4128 Cov.: 33

Gnomad AFR AF: 0.271

Gnomad AMI AF: 0.0844

Gnomad AMR AF: 0.219

Gnomad ASJ AF: 0.278

Gnomad EAS AF: 0.119

Gnomad SAS AF: 0.174

Gnomad FIN AF: 0.136

Gnomad MID AF: 0.239

Gnomad NFE AF: 0.228

Gnomad OTH AF: 0.220

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

GnomAD4 genome AF: 0.227 AC: 34542 AN: 152186 Hom.: 4130 Cov.: 33 AF XY: 0.220 AC XY: 16345 AN XY: 74424

African (AFR) AF: 0.271 AC: 11239 AN: 41494

American (AMR) AF: 0.219 AC: 3346 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.278 AC: 965 AN: 3470

East Asian (EAS) AF: 0.119 AC: 617 AN: 5178

South Asian (SAS) AF: 0.174 AC: 842 AN: 4826

European-Finnish (FIN) AF: 0.136 AC: 1444 AN: 10600

Middle Eastern (MID) AF: 0.240 AC: 70 AN: 292

European-Non Finnish (NFE) AF: 0.228 AC: 15484 AN: 68004

Other (OTH) AF: 0.217 AC: 458 AN: 2114

Alfa AF: 0.215 Hom.: 1898

Bravo AF: 0.231

Asia WGS AF: 0.153 AC: 533 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	3.4
DANN	Benign	0.83
PhyloP100		-0.040
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: rs4765864; hg19: chr12-2021395; COSMIC: COSV54958827;