12-1846620-G-C

Variant names:

• chr12-1846620-G-C
• rs11836202
• NM_172364.5:c.2316C>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.2316C>G​(p.Phe772Leu) 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. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. F772F) has been classified as Benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: CACNA2D4 NM_172364.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.0530
• Publications: 0 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):

• CACNA2D4-related retinopathy

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• retinal cone dystrophy 4

  Inheritance: Unknown, AR Classification: STRONG, MODERATE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), G2P, Laboratory for Molecular Medicine
• 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=0.24989498).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CACNA2D4	NM_172364.5	MANE Select	c.2316C>G	p.Phe772Leu	missense	Exon 24 of 38	NP_758952.4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CACNA2D4	ENST00000382722.10	TSL:1 MANE Select	c.2316C>G	p.Phe772Leu	missense	Exon 24 of 38	ENSP00000372169.4	Q7Z3S7-1
	CACNA2D4	ENST00000586184.5	TSL:5	c.2316C>G	p.Phe772Leu	missense	Exon 24 of 37	ENSP00000465060.1	Q7Z3S7-5
	CACNA2D4	ENST00000587995.5	TSL:5	c.2241C>G	p.Phe747Leu	missense	Exon 23 of 37	ENSP00000465372.1	K7EJY1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.90
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	17
DANN	Uncertain	1.0
DEOGEN2	Benign	0.15	T
Eigen	Benign	-0.22
Eigen_PC	Benign	-0.24
FATHMM_MKL	Benign	0.75	D
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.25	T
MetaSVM	Benign	-0.90	T
MutationAssessor	Uncertain	2.5	M
PhyloP100		-0.053
PrimateAI	Uncertain	0.59	T
PROVEAN	Uncertain	-4.0	D
REVEL	Benign	0.17
Sift	Benign	0.037	D
Sift4G	Uncertain	0.0090	D
Polyphen		0.85	P
Vest4		0.41
MutPred		0.56		Loss of catalytic residue at F772 (P = 0.0639)
MVP		0.15
MPC		0.17
ClinPred		0.98	D
GERP RS		-0.25
Varity_R		0.40
gMVP		0.54
Mutation Taster		=73/27	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs11836202; hg19: chr12-1955786;