Genetic Variant CACNA2D4:c.487-4C>A (chr12-1908041-G-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_172364.5(CACNA2D4):c.487-4C>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 0.00000206 in 1,455,530 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: not found (cov: 33)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

CACNA2D4
NM_172364.5 splice_region, intron

Scores

Splicing: ADA: 0.00004917

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.306

Variant links:

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 links:

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ACMG classification

Classification made for transcript

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=-0.81).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA2D4	NM_172364.5 link	c.487-4C>A		splice_region_variant, intron_variant	Intron 4 of 37	ENST00000382722.10	NP_758952.4	Q7Z3S7-1

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
CACNA2D4	ENST00000382722.10 link	c.487-4C>A	splice_region_variant, intron_variant	Intron 4 of 37	1	NM_172364.5	ENSP00000372169.4	Q7Z3S7-1
CACNA2D4	ENST00000586184.5 link	c.487-4C>A	splice_region_variant, intron_variant	Intron 4 of 36	5		ENSP00000465060.1	Q7Z3S7-5
CACNA2D4	ENST00000587995.5 link	c.487-4C>A	splice_region_variant, intron_variant	Intron 4 of 36	5		ENSP00000465372.1	K7EJY1
CACNA2D4	ENST00000585708.5 link	c.295-4C>A	splice_region_variant, intron_variant	Intron 4 of 36	5		ENSP00000467697.1	Q7Z3S7-6
CACNA2D4	ENST00000588077.5 link	c.295-4C>A	splice_region_variant, intron_variant	Intron 4 of 37	5		ENSP00000468530.1	Q7Z3S7-4
CACNA2D4	ENST00000444595.6 link	n.487-4C>A	splice_region_variant, intron_variant	Intron 4 of 36	1		ENSP00000403371.2	E7EUE0

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000813

AC:

AN:

245888

Hom.:

AF XY:

0.0000150

AC XY:

AN XY:

133298

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000180

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000206

AC:

AN:

1455530

Hom.:

Cov.:

AF XY:

0.00000277

AC XY:

AN XY:

722936

show subpopulations

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:

0.00000271

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.81

CADD

Benign

2.0

DANN

Benign

0.86

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000049

dbscSNV1_RF

Benign

0.0040

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

LitVar

Other links and lift over