NM_172364.5:c.2316C>G

Variant names:

• chr12-1846620-G-C
• NM_172364.5:c.2316C>G

Variant summary

Our verdict is Uncertain significance. Variant got 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 (★).

• 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

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.24989498).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA2D4	NM_172364.5	c.2316C>G	p.Phe772Leu	missense_variant	Exon 24 of 38	ENST00000382722.10	NP_758952.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA2D4	ENST00000382722.10	c.2316C>G	p.Phe772Leu	missense_variant	Exon 24 of 38	1	NM_172364.5	ENSP00000372169.4
CACNA2D4	ENST00000586184.5	c.2316C>G	p.Phe772Leu	missense_variant	Exon 24 of 37	5		ENSP00000465060.1
CACNA2D4	ENST00000587995.5	c.2241C>G	p.Phe747Leu	missense_variant	Exon 23 of 37	5		ENSP00000465372.1
CACNA2D4	ENST00000585708.5	c.2124C>G	p.Phe708Leu	missense_variant	Exon 24 of 37	5		ENSP00000467697.1
CACNA2D4	ENST00000588077.5	c.2124C>G	p.Phe708Leu	missense_variant	Exon 24 of 38	5		ENSP00000468530.1
CACNA2D4	ENST00000444595.6	n.*562C>G		non_coding_transcript_exon_variant	Exon 24 of 37	1		ENSP00000403371.2
CACNA2D4	ENST00000537784.5	n.156C>G		non_coding_transcript_exon_variant	Exon 2 of 15	1		ENSP00000440231.2
CACNA2D4	ENST00000444595.6	n.*562C>G		3_prime_UTR_variant	Exon 24 of 37	1		ENSP00000403371.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Nov 15, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with CACNA2D4-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. This sequence change replaces phenylalanine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 772 of the CACNA2D4 protein (p.Phe772Leu). -

Computational scores

Source: dbNSFP v4.3

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;T;T;T;T;T
MetaSVM	Benign	-0.90	T
MutationAssessor	Uncertain	2.5	M;.;.;M;.;.
PrimateAI	Uncertain	0.59	T
PROVEAN	Uncertain	-4.0	D;.;.;.;.;.
REVEL	Benign	0.17
Sift	Benign	0.037	D;.;.;.;.;.
Sift4G	Uncertain	0.0090	D;D;D;D;D;D
Polyphen		0.85	P;.;.;.;.;.
Vest4		0.41
MutPred		0.56		Loss of catalytic residue at F772 (P = 0.0639);.;.;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

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr12-1955786;