chr12-1793739-G-C

Variant names:

• chr12-1793739-G-C
• rs33912216
• NM_172364.5:c.3330C>G

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP7

The NM_172364.5(CACNA2D4):​c.3330C>G​(p.Gly1110Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,460,812 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. G1110G) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: CACNA2D4 NM_172364.5 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -5.38
• Publications: 9 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: Likely_benign. The variant received -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP7: Synonymous conserved (PhyloP=-5.38 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA2D4	NM_172364.5	c.3330C>G	p.Gly1110Gly	synonymous_variant	Exon 38 of 38	ENST00000382722.10	NP_758952.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA2D4	ENST00000382722.10	c.3330C>G	p.Gly1110Gly	synonymous_variant	Exon 38 of 38	1	NM_172364.5	ENSP00000372169.4
CACNA2D4	ENST00000587995.5	c.3255C>G	p.Gly1085Gly	synonymous_variant	Exon 37 of 37	5		ENSP00000465372.1
CACNA2D4	ENST00000588077.5	c.3138C>G	p.Gly1046Gly	synonymous_variant	Exon 38 of 38	5		ENSP00000468530.1
CACNA2D4	ENST00000536846.6	c.768C>G	p.Gly256Gly	synonymous_variant	Exon 12 of 12	5		ENSP00000468167.1
CACNA2D4	ENST00000538027.6	c.765C>G	p.Gly255Gly	synonymous_variant	Exon 12 of 12	5		ENSP00000443038.2
CACNA2D4	ENST00000538450.5	c.720C>G	p.Gly240Gly	synonymous_variant	Exon 11 of 11	2		ENSP00000446341.1
CACNA2D4	ENST00000444595.6	n.*1514C>G		non_coding_transcript_exon_variant	Exon 37 of 37	1		ENSP00000403371.2
CACNA2D4	ENST00000537784.5	n.*523C>G		non_coding_transcript_exon_variant	Exon 15 of 15	1		ENSP00000440231.2
CACNA2D4	ENST00000545595.6	n.*523C>G		non_coding_transcript_exon_variant	Exon 10 of 10	1		ENSP00000442329.2
CACNA2D4	ENST00000585385.5	n.*523C>G		non_coding_transcript_exon_variant	Exon 11 of 11	5		ENSP00000467333.1
CACNA2D4	ENST00000444595.6	n.*1514C>G		3_prime_UTR_variant	Exon 37 of 37	1		ENSP00000403371.2
CACNA2D4	ENST00000537784.5	n.*523C>G		3_prime_UTR_variant	Exon 15 of 15	1		ENSP00000440231.2
CACNA2D4	ENST00000545595.6	n.*523C>G		3_prime_UTR_variant	Exon 10 of 10	1		ENSP00000442329.2
CACNA2D4	ENST00000585385.5	n.*523C>G		3_prime_UTR_variant	Exon 11 of 11	5		ENSP00000467333.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000407 AC: 1 AN: 245934 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000291

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1460812 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 726740

African (AFR) AF: 0.00 AC: 0 AN: 33472

American (AMR) AF: 0.0000224 AC: 1 AN: 44682

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26114

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86228

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52792

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5666

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111810

Other (OTH) AF: 0.00 AC: 0 AN: 60350

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.0060
DANN	Benign	0.59
PhyloP100		-5.4

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.17		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: rs33912216; hg19: chr12-1902905;