rs61386831

Variant names:

• chr12-1885952-C-T
• rs61386831
• NM_172364.5:c.1068+13G>A

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.1068+13G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.104 in 1,600,026 control chromosomes in the GnomAD database, including 9,656 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.12 (1401 hom., cov: 31)
  • Exomes 𝑓: 0.10 (8255 hom.)
• Consequence: CACNA2D4 NM_172364.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -1.29
• Publications: 4 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

LOC124902858 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 12-1885952-C-T is Benign according to our data. Variant chr12-1885952-C-T is described in ClinVar as Benign. ClinVar VariationId is 262808.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.19 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CACNA2D4	NM_172364.5	MANE Select	c.1068+13G>A		intron	N/A	NP_758952.4

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CACNA2D4	ENST00000382722.10	TSL:1 MANE Select	c.1068+13G>A		intron	N/A	ENSP00000372169.4
	CACNA2D4	ENST00000586184.5	TSL:5	c.1068+13G>A		intron	N/A	ENSP00000465060.1
	CACNA2D4	ENST00000587995.5	TSL:5	c.1068+13G>A		intron	N/A	ENSP00000465372.1

Frequencies

GnomAD3 genomes AF: 0.123 AC: 18606 AN: 151844 Hom.: 1392 Cov.: 31

Gnomad AFR AF: 0.194

Gnomad AMI AF: 0.0493

Gnomad AMR AF: 0.0734

Gnomad ASJ AF: 0.106

Gnomad EAS AF: 0.0305

Gnomad SAS AF: 0.131

Gnomad FIN AF: 0.0826

Gnomad MID AF: 0.0854

Gnomad NFE AF: 0.106

Gnomad OTH AF: 0.102

GnomAD2 exomes AF: 0.0996 AC: 24360 AN: 244538 AF XY: 0.102

Gnomad AFR exome AF: 0.187

Gnomad AMR exome AF: 0.0488

Gnomad ASJ exome AF: 0.105

Gnomad EAS exome AF: 0.0336

Gnomad FIN exome AF: 0.0909

Gnomad NFE exome AF: 0.103

Gnomad OTH exome AF: 0.0997

GnomAD4 exome AF: 0.103 AC: 148529 AN: 1448064 Hom.: 8255 Cov.: 31 AF XY: 0.104 AC XY: 74660 AN XY: 720716

African (AFR) AF: 0.192 AC: 6369 AN: 33116

American (AMR) AF: 0.0508 AC: 2255 AN: 44384

Ashkenazi Jewish (ASJ) AF: 0.103 AC: 2686 AN: 25980

East Asian (EAS) AF: 0.0420 AC: 1662 AN: 39586

South Asian (SAS) AF: 0.137 AC: 11683 AN: 85218

European-Finnish (FIN) AF: 0.0908 AC: 4834 AN: 53260

Middle Eastern (MID) AF: 0.103 AC: 586 AN: 5684

European-Non Finnish (NFE) AF: 0.102 AC: 112101 AN: 1100912

Other (OTH) AF: 0.106 AC: 6353 AN: 59924

GnomAD4 genome AF: 0.123 AC: 18652 AN: 151962 Hom.: 1401 Cov.: 31 AF XY: 0.120 AC XY: 8880 AN XY: 74290

African (AFR) AF: 0.194 AC: 8033 AN: 41426

American (AMR) AF: 0.0732 AC: 1118 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.106 AC: 367 AN: 3468

East Asian (EAS) AF: 0.0306 AC: 158 AN: 5170

South Asian (SAS) AF: 0.132 AC: 630 AN: 4776

European-Finnish (FIN) AF: 0.0826 AC: 874 AN: 10578

Middle Eastern (MID) AF: 0.0850 AC: 25 AN: 294

European-Non Finnish (NFE) AF: 0.106 AC: 7182 AN: 67960

Other (OTH) AF: 0.105 AC: 220 AN: 2100

Alfa AF: 0.117 Hom.: 221

Bravo AF: 0.121

Asia WGS AF: 0.119 AC: 412 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.33
DANN	Benign	0.88
PhyloP100		-1.3
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: rs61386831; hg19: chr12-1995118; COSMIC: COSV54951187; COSMIC: COSV54951187;