rs55971855

Positions:

• chr12-1799683-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The ENST00000382722.10(CACNA2D4):​c.2987T>C​(p.Phe996Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0069 in 1,572,600 control chromosomes in the GnomAD database, including 54 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0051 (4 hom., cov: 32)
  • Exomes 𝑓: 0.0071 (50 hom.)
• Consequence: CACNA2D4 ENST00000382722.10 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 6.21

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.00739339).
• BP6: Variant 12-1799683-A-G is Benign according to our data. Variant chr12-1799683-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 96535.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-1799683-A-G is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00515 (784/152276) while in subpopulation NFE AF= 0.00787 (535/68016). AF 95% confidence interval is 0.00731. There are 4 homozygotes in gnomad4. There are 349 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA2D4	NM_172364.5	c.2987T>C	p.Phe996Ser	missense_variant	34/38	ENST00000382722.10	NP_758952.4
CACNA2D4	XM_011521041.3	c.2924T>C	p.Phe975Ser	missense_variant	33/36		XP_011519343.1
CACNA2D4	XM_047429897.1	c.2915T>C	p.Phe972Ser	missense_variant	33/36		XP_047285853.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA2D4	ENST00000382722.10	c.2987T>C	p.Phe996Ser	missense_variant	34/38	1	NM_172364.5	ENSP00000372169	P2

Frequencies

GnomAD3 genomes AF: 0.00515 AC: 783 AN: 152158 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.00159

Gnomad AMI AF: 0.00987

Gnomad AMR AF: 0.00700

Gnomad ASJ AF: 0.0104

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.00132

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00785

Gnomad OTH AF: 0.00431

GnomAD3 exomes AF: 0.00509 AC: 958 AN: 188040 Hom.: 5 AF XY: 0.00510 AC XY: 513 AN XY: 100580

Gnomad AFR exome AF: 0.000784

Gnomad AMR exome AF: 0.00411

Gnomad ASJ exome AF: 0.0141

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00112

Gnomad FIN exome AF: 0.00269

Gnomad NFE exome AF: 0.00744

Gnomad OTH exome AF: 0.00660

GnomAD4 exome AF: 0.00708 AC: 10060 AN: 1420324 Hom.: 50 Cov.: 32 AF XY: 0.00697 AC XY: 4896 AN XY: 702792

Gnomad4 AFR exome AF: 0.00139

Gnomad4 AMR exome AF: 0.00426

Gnomad4 ASJ exome AF: 0.0164

Gnomad4 EAS exome AF: 0.0000269

Gnomad4 SAS exome AF: 0.00118

Gnomad4 FIN exome AF: 0.00231

Gnomad4 NFE exome AF: 0.00795

Gnomad4 OTH exome AF: 0.00769

GnomAD4 genome AF: 0.00515 AC: 784 AN: 152276 Hom.: 4 Cov.: 32 AF XY: 0.00469 AC XY: 349 AN XY: 74454

Gnomad4 AFR AF: 0.00159

Gnomad4 AMR AF: 0.00699

Gnomad4 ASJ AF: 0.0104

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00125

Gnomad4 FIN AF: 0.00132

Gnomad4 NFE AF: 0.00787

Gnomad4 OTH AF: 0.00427

Alfa AF: 0.00801 Hom.: 8

Bravo AF: 0.00558

TwinsUK AF: 0.00809 AC: 30

ALSPAC AF: 0.0106 AC: 41

ESP6500AA AF: 0.00143 AC: 6

ESP6500EA AF: 0.00631 AC: 53

ExAC AF: 0.00359 AC: 427

Asia WGS AF: 0.00202 AC: 8 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2024	CACNA2D4: BS2 -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 02, 2013	- -

Retinal cone dystrophy 4 Benign:1

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.39
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.17
CADD	Pathogenic	26
DANN	Uncertain	0.98
DEOGEN2	Benign	0.039	T;.;.;.;.;.;.
Eigen	Benign	-0.050
Eigen_PC	Benign	-0.028
FATHMM_MKL	Uncertain	0.94	D
MetaRNN	Benign	0.0074	T;T;T;T;T;T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	1.9	L;.;.;.;.;L;.
MutationTaster	Benign	0.97	D;D;D;D;D;D;D
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	-1.7	N;N;.;.;.;.;.
REVEL	Benign	0.18
Sift	Benign	0.39	T;D;.;.;.;.;.
Sift4G	Uncertain	0.041	D;D;T;D;D;D;D
Polyphen		0.93	P;P;.;B;.;.;.
Vest4		0.49
MVP		0.33
MPC		0.26
ClinPred		0.016	T
GERP RS		4.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.20
gMVP		0.55

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs55971855; hg19: chr12-1908849;