chr12-1886237-T-C

Variant names:

• chr12-1886237-T-C
• rs10735005
• NM_172364.5:c.979A>G

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.979A>G​(p.Ile327Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.896 in 1,612,314 control chromosomes in the GnomAD database, including 648,295 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

• Frequency:
  • Genomes: 𝑓 0.92 (64041 hom., cov: 30)
  • Exomes 𝑓: 0.89 (584254 hom.)
• Consequence: CACNA2D4 NM_172364.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 3.20
• Publications: 39 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

LOC124902858 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=1.9109855E-6).
• BP6: Variant 12-1886237-T-C is Benign according to our data. Variant chr12-1886237-T-C is described in ClinVar as Benign. ClinVar VariationId is 262820.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.976 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.979A>G	p.Ile327Val	missense	Exon 8 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.979A>G	p.Ile327Val	missense	Exon 8 of 38	ENSP00000372169.4	Q7Z3S7-1
	CACNA2D4	ENST00000586184.5	TSL:5	c.979A>G	p.Ile327Val	missense	Exon 8 of 37	ENSP00000465060.1	Q7Z3S7-5
	CACNA2D4	ENST00000587995.5	TSL:5	c.979A>G	p.Ile327Val	missense	Exon 8 of 37	ENSP00000465372.1	K7EJY1

Frequencies

GnomAD3 genomes AF: 0.916 AC: 139265 AN: 152006 Hom.: 63975 Cov.: 30

Gnomad AFR AF: 0.978

Gnomad AMI AF: 0.834

Gnomad AMR AF: 0.892

Gnomad ASJ AF: 0.857

Gnomad EAS AF: 0.999

Gnomad SAS AF: 0.910

Gnomad FIN AF: 0.894

Gnomad MID AF: 0.844

Gnomad NFE AF: 0.887

Gnomad OTH AF: 0.889

GnomAD2 exomes AF: 0.903 AC: 225118 AN: 249246 AF XY: 0.901

Gnomad AFR exome AF: 0.982

Gnomad AMR exome AF: 0.890

Gnomad ASJ exome AF: 0.845

Gnomad EAS exome AF: 0.999

Gnomad FIN exome AF: 0.891

Gnomad NFE exome AF: 0.888

Gnomad OTH exome AF: 0.881

GnomAD4 exome AF: 0.894 AC: 1305653 AN: 1460190 Hom.: 584254 Cov.: 48 AF XY: 0.894 AC XY: 649146 AN XY: 726462

African (AFR) AF: 0.984 AC: 32922 AN: 33458

American (AMR) AF: 0.892 AC: 39885 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.850 AC: 22210 AN: 26124

East Asian (EAS) AF: 0.999 AC: 39664 AN: 39686

South Asian (SAS) AF: 0.907 AC: 78251 AN: 86240

European-Finnish (FIN) AF: 0.886 AC: 47291 AN: 53398

Middle Eastern (MID) AF: 0.870 AC: 5016 AN: 5764

European-Non Finnish (NFE) AF: 0.888 AC: 986155 AN: 1110486

Other (OTH) AF: 0.900 AC: 54259 AN: 60312

GnomAD4 genome AF: 0.916 AC: 139390 AN: 152124 Hom.: 64041 Cov.: 30 AF XY: 0.916 AC XY: 68131 AN XY: 74368

African (AFR) AF: 0.978 AC: 40594 AN: 41504

American (AMR) AF: 0.892 AC: 13642 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.857 AC: 2973 AN: 3470

East Asian (EAS) AF: 0.999 AC: 5165 AN: 5170

South Asian (SAS) AF: 0.911 AC: 4377 AN: 4806

European-Finnish (FIN) AF: 0.894 AC: 9447 AN: 10572

Middle Eastern (MID) AF: 0.849 AC: 248 AN: 292

European-Non Finnish (NFE) AF: 0.887 AC: 60306 AN: 67992

Other (OTH) AF: 0.891 AC: 1881 AN: 2112

Alfa AF: 0.894 Hom.: 230211

Bravo AF: 0.919

TwinsUK AF: 0.894 AC: 3316

ALSPAC AF: 0.887 AC: 3417

ESP6500AA AF: 0.977 AC: 4072

ESP6500EA AF: 0.886 AC: 7459

ExAC AF: 0.906 AC: 109585

Asia WGS AF: 0.961 AC: 3344 AN: 3478

EpiCase AF: 0.876

EpiControl AF: 0.874

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	2	Retinal cone dystrophy 4 (2)
-	-	1	Cone dystrophy 3 (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.051
BayesDel_addAF	Benign	-0.73	T
BayesDel_noAF	Benign	-0.73
CADD	Benign	9.5
DANN	Benign	0.49
DEOGEN2	Benign	0.052	T
Eigen	Benign	-0.82
Eigen_PC	Benign	-0.50
FATHMM_MKL	Benign	0.23	N
MetaRNN	Benign	0.0000019	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	-2.0	N
PhyloP100		3.2
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	0.44	N
REVEL	Benign	0.11
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.054
MPC		0.11
ClinPred		0.0026	T
GERP RS		5.2
Varity_R		0.092
gMVP		0.26
Mutation Taster		=83/17	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: rs10735005; hg19: chr12-1995403; COSMIC: COSV54956232; COSMIC: COSV54956232;