12-1800379-C-T

Position:

• chr12-1800379-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_172364.5(CACNA2D4):​c.2921+7G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,178 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
• Consequence: CACNA2D4 NM_172364.5 splice_region, intron
• Scores: Splicing: ADA: 0.00003756
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.332

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 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA2D4	NM_172364.5	c.2921+7G>A		splice_region_variant, intron_variant		ENST00000382722.10	NP_758952.4
CACNA2D4	XM_011521041.3	c.2858+7G>A		splice_region_variant, intron_variant			XP_011519343.1
CACNA2D4	XM_047429897.1	c.2849+7G>A		splice_region_variant, intron_variant			XP_047285853.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA2D4	ENST00000382722.10	c.2921+7G>A		splice_region_variant, intron_variant		1	NM_172364.5	ENSP00000372169.4
CACNA2D4	ENST00000586184.5	c.2921+7G>A		splice_region_variant, intron_variant		5		ENSP00000465060.1
CACNA2D4	ENST00000587995.5	c.2846+7G>A		splice_region_variant, intron_variant		5		ENSP00000465372.1
CACNA2D4	ENST00000585708.5	c.2729+7G>A		splice_region_variant, intron_variant		5		ENSP00000467697.1
CACNA2D4	ENST00000588077.5	c.2729+7G>A		splice_region_variant, intron_variant		5		ENSP00000468530.1
CACNA2D4	ENST00000536846.6	c.359+7G>A		splice_region_variant, intron_variant		5		ENSP00000468167.1
CACNA2D4	ENST00000538027.6	c.356+7G>A		splice_region_variant, intron_variant		5		ENSP00000443038.2
CACNA2D4	ENST00000538450.5	c.311+7G>A		splice_region_variant, intron_variant		2		ENSP00000446341.1
CACNA2D4	ENST00000444595.6	n.*1105+7G>A		splice_region_variant, intron_variant		1		ENSP00000403371.2
CACNA2D4	ENST00000537784.5	n.*114+7G>A		splice_region_variant, intron_variant		1		ENSP00000440231.2
CACNA2D4	ENST00000545595.6	n.*114+7G>A		splice_region_variant, intron_variant		1		ENSP00000442329.2
CACNA2D4	ENST00000585385.5	n.*114+7G>A		splice_region_variant, intron_variant		5		ENSP00000467333.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152178 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 32

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152178 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74332

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	9.6
DANN	Benign	0.46
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000038
dbscSNV1_RF	Benign	0.0
SpliceAI score (max)		0.11		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs202022529; hg19: chr12-1909545;