rs10735005

chr12-1886237-T-Cchr12-1886237-T-G

Variant summary

Our verdict is Benign. Variant got -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. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• 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:5
• Conservation: PhyloP100: 3.20

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]

LOC124902858 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -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 id is 262820.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-1886237-T-C is described in Lovd as [Benign].
• 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/exons	MANE	UniProt
CACNA2D4	NM_172364.5	c.979A>G	p.Ile327Val	missense_variant	8/38	ENST00000382722.10
LOC124902858	XR_007063158.1	n.295-19T>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CACNA2D4	ENST00000382722.10	c.979A>G	p.Ile327Val	missense_variant	8/38	1	NM_172364.5	P2

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

GnomAD3 exomes AF: 0.903 AC: 225118 AN: 249246 Hom.: 101899 AF XY: 0.901 AC XY: 121784 AN XY: 135208

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 SAS exome AF: 0.912

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

Gnomad4 AFR exome AF: 0.984

Gnomad4 AMR exome AF: 0.892

Gnomad4 ASJ exome AF: 0.850

Gnomad4 EAS exome AF: 0.999

Gnomad4 SAS exome AF: 0.907

Gnomad4 FIN exome AF: 0.886

Gnomad4 NFE exome AF: 0.888

Gnomad4 OTH exome AF: 0.900

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

Gnomad4 AFR AF: 0.978

Gnomad4 AMR AF: 0.892

Gnomad4 ASJ AF: 0.857

Gnomad4 EAS AF: 0.999

Gnomad4 SAS AF: 0.911

Gnomad4 FIN AF: 0.894

Gnomad4 NFE AF: 0.887

Gnomad4 OTH AF: 0.891

Alfa AF: 0.888 Hom.: 153626

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:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Retinal cone dystrophy 4 Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 14, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	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 specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Cone dystrophy 3 Benign:1

Benign, criteria provided, single submitter

clinical testing

Mendelics

May 28, 2019

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

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;.
MutationTaster	Benign	1.0	P;P;P;P;P;P
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

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

Publications

LitVar

Other links and lift over

dbSNP: rs10735005; hg19: chr12-1995403; COSMIC: COSV54956232; COSMIC: COSV54956232;