12-1856203-G-C

Variant names:

• chr12-1856203-G-C
• rs2286372
• NM_172364.5:c.2035C>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_172364.5(CACNA2D4):​c.2035C>G​(p.Leu679Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict 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. L679L) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: CACNA2D4 NM_172364.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.137
• Publications: 15 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.1868614).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA2D4	NM_172364.5	c.2035C>G	p.Leu679Val	missense_variant	Exon 21 of 38	ENST00000382722.10	NP_758952.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA2D4	ENST00000382722.10	c.2035C>G	p.Leu679Val	missense_variant	Exon 21 of 38	1	NM_172364.5	ENSP00000372169.4
CACNA2D4	ENST00000586184.5	c.2035C>G	p.Leu679Val	missense_variant	Exon 21 of 37	5		ENSP00000465060.1
CACNA2D4	ENST00000587995.5	c.1960C>G	p.Leu654Val	missense_variant	Exon 20 of 37	5		ENSP00000465372.1
CACNA2D4	ENST00000585708.5	c.1843C>G	p.Leu615Val	missense_variant	Exon 21 of 37	5		ENSP00000467697.1
CACNA2D4	ENST00000588077.5	c.1843C>G	p.Leu615Val	missense_variant	Exon 21 of 38	5		ENSP00000468530.1
CACNA2D4	ENST00000444595.6	n.*281C>G		non_coding_transcript_exon_variant	Exon 21 of 37	1		ENSP00000403371.2
CACNA2D4	ENST00000444595.6	n.*281C>G		3_prime_UTR_variant	Exon 21 of 37	1		ENSP00000403371.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.092
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	18
DANN	Benign	0.48
DEOGEN2	Benign	0.059	T;.;.;.;.;.
Eigen	Benign	-0.83
Eigen_PC	Benign	-0.74
FATHMM_MKL	Benign	0.70	D
LIST_S2	Benign	0.0	.;.;.;.;.;.
M_CAP	Benign	0.0099	T
MetaRNN	Benign	0.19	T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.1	L;.;.;L;.;.
PhyloP100		0.14
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-0.35	N;.;.;.;.;.
REVEL	Benign	0.033
Sift	Benign	0.84	T;.;.;.;.;.
Sift4G	Benign	0.49	T;T;T;T;T;T
Vest4		0.12
ClinPred		0.054	T
GERP RS		2.5
Varity_R		0.048
gMVP		0.50
Mutation Taster		=93/7	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs2286372; hg19: chr12-1965369;