NM_172364.5:c.2087A>C

Variant names:

• chr12-1856077-T-G
• rs115228472
• NM_172364.5:c.2087A>C

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_172364.5(CACNA2D4):​c.2087A>C​(p.His696Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H696Y) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: CACNA2D4 NM_172364.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 8.02
• 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):

• 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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.772

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.2087A>C	p.His696Pro	missense	Exon 22 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.2087A>C	p.His696Pro	missense	Exon 22 of 38	ENSP00000372169.4	Q7Z3S7-1
	CACNA2D4	ENST00000586184.5	TSL:5	c.2087A>C	p.His696Pro	missense	Exon 22 of 37	ENSP00000465060.1	Q7Z3S7-5
	CACNA2D4	ENST00000587995.5	TSL:5	c.2012A>C	p.His671Pro	missense	Exon 21 of 37	ENSP00000465372.1	K7EJY1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 51

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.68
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.060
CADD	Pathogenic	26
DANN	Uncertain	0.98
DEOGEN2	Benign	0.24	T
Eigen	Uncertain	0.63
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Pathogenic	0.97	D
M_CAP	Benign	0.040	D
MetaRNN	Pathogenic	0.77	D
MetaSVM	Benign	-0.82	T
MutationAssessor	Uncertain	2.7	M
PhyloP100		8.0
PrimateAI	Benign	0.44	T
PROVEAN	Pathogenic	-6.9	D
REVEL	Uncertain	0.44
Sift	Benign	0.060	T
Sift4G	Uncertain	0.025	D
Polyphen		1.0	D
Vest4		0.88
MutPred		0.46		Gain of relative solvent accessibility (P = 0.0249)
MVP		0.32
MPC		0.74
ClinPred		0.99	D
GERP RS		4.2
Varity_R		0.75
gMVP		0.85
Mutation Taster		=79/21	polymorphism

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: rs115228472; hg19: chr12-1965243;