chr12-1832290-T-C

Position:

• chr12-1832290-T-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_172364.5(CACNA2D4):​c.2551+8449A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.738 in 152,082 control chromosomes in the GnomAD database, including 42,190 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.74 (42190 hom., cov: 32)
• Consequence: CACNA2D4 NM_172364.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.60

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]

LRTM2 (HGNC:32443): (leucine rich repeats and transmembrane domains 2) Predicted to enable Roundabout binding activity and heparin binding activity. Predicted to be involved in axon guidance and negative chemotaxis. Predicted to act upstream of or within positive regulation of synapse assembly. Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

CACNA2D4 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.966 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA2D4	NM_172364.5	c.2551+8449A>G		intron_variant		ENST00000382722.10	NP_758952.4
LRTM2	NM_001039029.3	c.658+765T>C		intron_variant		ENST00000299194.6	NP_001034118.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA2D4	ENST00000382722.10	c.2551+8449A>G		intron_variant		1	NM_172364.5	ENSP00000372169.4
LRTM2	ENST00000299194.6	c.658+765T>C		intron_variant		2	NM_001039029.3	ENSP00000299194.1
CACNA2D4	ENST00000586184.5	c.2551+8449A>G		intron_variant		5		ENSP00000465060.1
CACNA2D4	ENST00000587995.5	c.2476+8449A>G		intron_variant		5		ENSP00000465372.1
CACNA2D4	ENST00000585708.5	c.2359+8449A>G		intron_variant		5		ENSP00000467697.1
CACNA2D4	ENST00000588077.5	c.2359+8449A>G		intron_variant		5		ENSP00000468530.1
CACNA2D4	ENST00000444595.6	n.*797+8449A>G		intron_variant		1		ENSP00000403371.2
CACNA2D4	ENST00000537784.5	n.391+8449A>G		intron_variant		1		ENSP00000440231.2

Frequencies

GnomAD3 genomes AF: 0.739 AC: 112234 AN: 151964 Hom.: 42170 Cov.: 32

Gnomad AFR AF: 0.613

Gnomad AMI AF: 0.833

Gnomad AMR AF: 0.803

Gnomad ASJ AF: 0.730

Gnomad EAS AF: 0.988

Gnomad SAS AF: 0.861

Gnomad FIN AF: 0.838

Gnomad MID AF: 0.750

Gnomad NFE AF: 0.756

Gnomad OTH AF: 0.748

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.738 AC: 112295 AN: 152082 Hom.: 42190 Cov.: 32 AF XY: 0.749 AC XY: 55644 AN XY: 74340

Gnomad4 AFR AF: 0.613

Gnomad4 AMR AF: 0.803

Gnomad4 ASJ AF: 0.730

Gnomad4 EAS AF: 0.989

Gnomad4 SAS AF: 0.860

Gnomad4 FIN AF: 0.838

Gnomad4 NFE AF: 0.756

Gnomad4 OTH AF: 0.750

Alfa AF: 0.754 Hom.: 16553

Bravo AF: 0.732

Asia WGS AF: 0.899 AC: 3127 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.17
DANN	Benign	0.30

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs4765847; hg19: chr12-1941456;