12-1856203-G-T

Variant names:

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

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_172364.5(CACNA2D4):​c.2035C>A​(p.Leu679Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,690 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: CACNA2D4 NM_172364.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.137

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA2D4	NM_172364.5	c.2035C>A	p.Leu679Met	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>A	p.Leu679Met	missense_variant	Exon 21 of 38	1	NM_172364.5	ENSP00000372169.4
CACNA2D4	ENST00000586184.5	c.2035C>A	p.Leu679Met	missense_variant	Exon 21 of 37	5		ENSP00000465060.1
CACNA2D4	ENST00000587995.5	c.1960C>A	p.Leu654Met	missense_variant	Exon 20 of 37	5		ENSP00000465372.1
CACNA2D4	ENST00000585708.5	c.1843C>A	p.Leu615Met	missense_variant	Exon 21 of 37	5		ENSP00000467697.1
CACNA2D4	ENST00000588077.5	c.1843C>A	p.Leu615Met	missense_variant	Exon 21 of 38	5		ENSP00000468530.1
CACNA2D4	ENST00000444595.6	n.*281C>A		non_coding_transcript_exon_variant	Exon 21 of 37	1		ENSP00000403371.2
CACNA2D4	ENST00000444595.6	n.*281C>A		3_prime_UTR_variant	Exon 21 of 37	1		ENSP00000403371.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461690 Hom.: 0 Cov.: 33 AF XY: 0.00000275 AC XY: 2 AN XY: 727126

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.45
CADD	Uncertain	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.14	T;.;.;.;.;.
Eigen	Benign	0.0044
Eigen_PC	Benign	-0.14
FATHMM_MKL	Uncertain	0.78	D
M_CAP	Benign	0.023	T
MetaRNN	Uncertain	0.58	D;D;D;D;D;D
MetaSVM	Benign	-0.81	T
MutationAssessor	Uncertain	2.5	M;.;.;M;.;.
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-0.71	N;.;.;.;.;.
REVEL	Benign	0.11
Sift	Benign	0.13	T;.;.;.;.;.
Sift4G	Uncertain	0.055	T;D;T;D;T;D
Polyphen		0.98	D;.;.;.;.;.
Vest4		0.38
MutPred		0.48		Gain of loop (P = 0.0502);.;.;Gain of loop (P = 0.0502);.;.;
MVP		0.30
MPC		0.46
ClinPred		0.71	D
GERP RS		2.5
Varity_R		0.090
gMVP		0.43

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: chr12-1965369;