rs10735005

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chr12-1886237-T-C
• chr12-1886237-T-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):

• 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 (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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA2D4	NM_172364.5	c.979A>G	p.Ile327Val	missense_variant	Exon 8 of 38	ENST00000382722.10	NP_758952.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA2D4	ENST00000382722.10	c.979A>G	p.Ile327Val	missense_variant	Exon 8 of 38	1	NM_172364.5	ENSP00000372169.4
CACNA2D4	ENST00000586184.5	c.979A>G	p.Ile327Val	missense_variant	Exon 8 of 37	5		ENSP00000465060.1
CACNA2D4	ENST00000587995.5	c.979A>G	p.Ile327Val	missense_variant	Exon 8 of 37	5		ENSP00000465372.1
CACNA2D4	ENST00000585708.5	c.787A>G	p.Ile263Val	missense_variant	Exon 8 of 37	5		ENSP00000467697.1
CACNA2D4	ENST00000588077.5	c.787A>G	p.Ile263Val	missense_variant	Exon 8 of 38	5		ENSP00000468530.1
CACNA2D4	ENST00000444595.6	n.979A>G		non_coding_transcript_exon_variant	Exon 8 of 37	1		ENSP00000403371.2

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

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Retinal cone dystrophy 4 Benign:2

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. -

Jul 14, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cone dystrophy 3 Benign:1

May 28, 2019

Mendelics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

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;T;T;T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	-2.0	N;.;.;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;T;T;T;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;