rs80092457

Variant names:

• chr12-1793763-C-A
• rs80092457
• NM_172364.5:c.3310-4G>T

Your query was ambiguous. Multiple possible variants found:

• chr12-1793763-C-A
• chr12-1793763-C-T

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BP6

The NM_172364.5(CACNA2D4):​c.3310-4G>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000048 in 1,459,574 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. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: CACNA2D4 NM_172364.5 splice_region, intron
• Scores: Splicing: ADA: 0.00003845
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: -2.04
• Publications: 5 publications found

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 Gene-Disease associations (from GenCC):

• inherited retinal dystrophy

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• retinal cone dystrophy 4

  Inheritance: AR, Unknown Classification: STRONG, MODERATE, LIMITED Submitted by: Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), G2P
• cone-rod dystrophy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 12-1793763-C-A is Benign according to our data. Variant chr12-1793763-C-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 883548.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA2D4	NM_172364.5	c.3310-4G>T		splice_region_variant, intron_variant	Intron 37 of 37	ENST00000382722.10	NP_758952.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA2D4	ENST00000382722.10	c.3310-4G>T		splice_region_variant, intron_variant	Intron 37 of 37	1	NM_172364.5	ENSP00000372169.4
CACNA2D4	ENST00000587995.5	c.3235-4G>T		splice_region_variant, intron_variant	Intron 36 of 36	5		ENSP00000465372.1
CACNA2D4	ENST00000588077.5	c.3118-4G>T		splice_region_variant, intron_variant	Intron 37 of 37	5		ENSP00000468530.1
CACNA2D4	ENST00000536846.6	c.748-4G>T		splice_region_variant, intron_variant	Intron 11 of 11	5		ENSP00000468167.1
CACNA2D4	ENST00000538027.6	c.745-4G>T		splice_region_variant, intron_variant	Intron 11 of 11	5		ENSP00000443038.2
CACNA2D4	ENST00000538450.5	c.700-4G>T		splice_region_variant, intron_variant	Intron 10 of 10	2		ENSP00000446341.1
CACNA2D4	ENST00000444595.6	n.*1494-4G>T		splice_region_variant, intron_variant	Intron 36 of 36	1		ENSP00000403371.2
CACNA2D4	ENST00000537784.5	n.*503-4G>T		splice_region_variant, intron_variant	Intron 14 of 14	1		ENSP00000440231.2
CACNA2D4	ENST00000545595.6	n.*503-4G>T		splice_region_variant, intron_variant	Intron 9 of 9	1		ENSP00000442329.2
CACNA2D4	ENST00000585385.5	n.*503-4G>T		splice_region_variant, intron_variant	Intron 10 of 10	5		ENSP00000467333.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000480 AC: 7 AN: 1459574 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 726164

African (AFR) AF: 0.00 AC: 0 AN: 33430

American (AMR) AF: 0.00 AC: 0 AN: 44688

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26086

East Asian (EAS) AF: 0.00 AC: 0 AN: 39686

South Asian (SAS) AF: 0.00 AC: 0 AN: 86188

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52702

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5416

European-Non Finnish (NFE) AF: 0.00000630 AC: 7 AN: 1111092

Other (OTH) AF: 0.00 AC: 0 AN: 60286

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Retinal cone dystrophy 4 Uncertain:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

not provided Benign:1

Jul 14, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.067
DANN	Benign	0.60
PhyloP100		-2.0
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)		0.19		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs80092457; hg19: chr12-1902929;