rs2058111

Variant names:

• chr12-1793600-T-G
• rs2058111
• ENST00000444595.6:n.*1653A>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000444595.6(CACNA2D4):​n.*1653A>C variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.529 in 1,504,018 control chromosomes in the GnomAD database, including 216,354 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.45 (16908 hom., cov: 33)
  • Exomes 𝑓: 0.54 (199446 hom.)
• Consequence: CACNA2D4 ENST00000444595.6 non_coding_transcript_exon
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.466
• Publications: 22 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 12-1793600-T-G is Benign according to our data. Variant chr12-1793600-T-G is described in ClinVar as Benign. ClinVar VariationId is 307828.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.56 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA2D4	NM_172364.5	c.*55A>C		3_prime_UTR_variant	Exon 38 of 38	ENST00000382722.10	NP_758952.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA2D4	ENST00000444595.6	n.*1653A>C		non_coding_transcript_exon_variant	Exon 37 of 37	1		ENSP00000403371.2
CACNA2D4	ENST00000537784.5	n.*662A>C		non_coding_transcript_exon_variant	Exon 15 of 15	1		ENSP00000440231.2
CACNA2D4	ENST00000545595.6	n.*662A>C		non_coding_transcript_exon_variant	Exon 10 of 10	1		ENSP00000442329.2
CACNA2D4	ENST00000585385.5	n.*662A>C		non_coding_transcript_exon_variant	Exon 11 of 11	5		ENSP00000467333.1
CACNA2D4	ENST00000382722.10	c.*55A>C		3_prime_UTR_variant	Exon 38 of 38	1	NM_172364.5	ENSP00000372169.4
CACNA2D4	ENST00000587995.5	c.*55A>C		3_prime_UTR_variant	Exon 37 of 37	5		ENSP00000465372.1
CACNA2D4	ENST00000588077.5	c.*55A>C		3_prime_UTR_variant	Exon 38 of 38	5		ENSP00000468530.1
CACNA2D4	ENST00000538450.5	c.*55A>C		3_prime_UTR_variant	Exon 11 of 11	2		ENSP00000446341.1
CACNA2D4	ENST00000444595.6	n.*1653A>C		3_prime_UTR_variant	Exon 37 of 37	1		ENSP00000403371.2
CACNA2D4	ENST00000537784.5	n.*662A>C		3_prime_UTR_variant	Exon 15 of 15	1		ENSP00000440231.2
CACNA2D4	ENST00000545595.6	n.*662A>C		3_prime_UTR_variant	Exon 10 of 10	1		ENSP00000442329.2
CACNA2D4	ENST00000585385.5	n.*662A>C		3_prime_UTR_variant	Exon 11 of 11	5		ENSP00000467333.1
CACNA2D4	ENST00000536846.6	c.*55A>C		downstream_gene_variant		5		ENSP00000468167.1
CACNA2D4	ENST00000538027.6	c.*55A>C		downstream_gene_variant		5		ENSP00000443038.2

Frequencies

GnomAD3 genomes AF: 0.446 AC: 67796 AN: 152000 Hom.: 16906 Cov.: 33

Gnomad AFR AF: 0.221

Gnomad AMI AF: 0.622

Gnomad AMR AF: 0.400

Gnomad ASJ AF: 0.588

Gnomad EAS AF: 0.482

Gnomad SAS AF: 0.453

Gnomad FIN AF: 0.551

Gnomad MID AF: 0.547

Gnomad NFE AF: 0.564

Gnomad OTH AF: 0.432

GnomAD4 exome AF: 0.539 AC: 728131 AN: 1351900 Hom.: 199446 Cov.: 20 AF XY: 0.538 AC XY: 365165 AN XY: 678280

African (AFR) AF: 0.207 AC: 6523 AN: 31464

American (AMR) AF: 0.407 AC: 17910 AN: 44046

Ashkenazi Jewish (ASJ) AF: 0.590 AC: 14979 AN: 25392

East Asian (EAS) AF: 0.522 AC: 20429 AN: 39170

South Asian (SAS) AF: 0.457 AC: 38304 AN: 83906

European-Finnish (FIN) AF: 0.544 AC: 28727 AN: 52808

Middle Eastern (MID) AF: 0.542 AC: 3019 AN: 5570

European-Non Finnish (NFE) AF: 0.561 AC: 568452 AN: 1012748

Other (OTH) AF: 0.524 AC: 29788 AN: 56796

GnomAD4 genome AF: 0.446 AC: 67803 AN: 152118 Hom.: 16908 Cov.: 33 AF XY: 0.446 AC XY: 33133 AN XY: 74334

African (AFR) AF: 0.221 AC: 9165 AN: 41526

American (AMR) AF: 0.400 AC: 6117 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.588 AC: 2041 AN: 3470

East Asian (EAS) AF: 0.483 AC: 2490 AN: 5160

South Asian (SAS) AF: 0.453 AC: 2180 AN: 4812

European-Finnish (FIN) AF: 0.551 AC: 5820 AN: 10566

Middle Eastern (MID) AF: 0.558 AC: 164 AN: 294

European-Non Finnish (NFE) AF: 0.564 AC: 38350 AN: 67968

Other (OTH) AF: 0.430 AC: 910 AN: 2114

Alfa AF: 0.509 Hom.: 9573

Bravo AF: 0.424

Asia WGS AF: 0.428 AC: 1492 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Retinal cone dystrophy 4 Benign:2

Jul 14, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.

not provided Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.93
DANN	Benign	0.64
PhyloP100		-0.47
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
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

Other links and lift over

dbSNP: rs2058111; hg19: chr12-1902766; COSMIC: COSV54951527; COSMIC: COSV54951527;