NM_172364.5:c.*55A>C

Variant names:

• chr12-1793600-T-G
• rs2058111
• NM_172364.5:c.*55A>C

Variant summary

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

The NM_172364.5(CACNA2D4):​c.*55A>C variant causes a 3 prime UTR 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 NM_172364.5 3_prime_UTR
• 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):

• CACNA2D4-related retinopathy

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

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_172364.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CACNA2D4	NM_172364.5	MANE Select	c.*55A>C		3_prime_UTR	Exon 38 of 38	NP_758952.4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CACNA2D4	ENST00000382722.10	TSL:1 MANE Select	c.*55A>C		3_prime_UTR	Exon 38 of 38	ENSP00000372169.4	Q7Z3S7-1
	CACNA2D4	ENST00000587995.5	TSL:5	c.*55A>C		3_prime_UTR	Exon 37 of 37	ENSP00000465372.1	K7EJY1
	CACNA2D4	ENST00000588077.5	TSL:5	c.*55A>C		3_prime_UTR	Exon 38 of 38	ENSP00000468530.1	Q7Z3S7-4

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

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Retinal cone dystrophy 4 (2)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

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;