rs758160

Variant names:

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_172364.5(CACNA2D4):c.1866G>A(p.Pro622Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.1 in 1,610,304 control chromosomes in the GnomAD database, including 8,722 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.11 ( 995 hom., cov: 32)

Exomes 𝑓: 0.10 ( 7727 hom. )

Consequence

CACNA2D4
NM_172364.5 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: -5.73

Variant links:

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 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.69).

BP6

Variant 12-1874616-C-T is Benign according to our data. Variant chr12-1874616-C-T is described in ClinVar as [Benign]. Clinvar id is 262811.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-5.73 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.138 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA2D4	NM_172364.5 link	c.1866G>A	p.Pro622Pro	synonymous_variant	Exon 18 of 38	ENST00000382722.10	NP_758952.4	Q7Z3S7-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
CACNA2D4	ENST00000382722.10 link	c.1866G>A	p.Pro622Pro	synonymous_variant	Exon 18 of 38	1	NM_172364.5	ENSP00000372169.4	Q7Z3S7-1
CACNA2D4	ENST00000586184.5 link	c.1866G>A	p.Pro622Pro	synonymous_variant	Exon 18 of 37	5		ENSP00000465060.1	Q7Z3S7-5
CACNA2D4	ENST00000587995.5 link	c.1791G>A	p.Pro597Pro	synonymous_variant	Exon 17 of 37	5		ENSP00000465372.1	K7EJY1
CACNA2D4	ENST00000585708.5 link	c.1674G>A	p.Pro558Pro	synonymous_variant	Exon 18 of 37	5		ENSP00000467697.1	Q7Z3S7-6
CACNA2D4	ENST00000588077.5 link	c.1674G>A	p.Pro558Pro	synonymous_variant	Exon 18 of 38	5		ENSP00000468530.1	Q7Z3S7-4
CACNA2D4	ENST00000444595.6 link	n.*112G>A		non_coding_transcript_exon_variant	Exon 18 of 37	1		ENSP00000403371.2	E7EUE0
CACNA2D4	ENST00000444595.6 link	n.*112G>A		3_prime_UTR_variant	Exon 18 of 37	1		ENSP00000403371.2	E7EUE0

Frequencies

GnomAD3 genomes

AF:

0.105

AC:

16012

AN:

152094

Hom.:

986

Cov.:

show subpopulations

Gnomad AFR

AF:

0.141

Gnomad AMI

AF:

0.0493

Gnomad AMR

AF:

0.0644

Gnomad ASJ

AF:

0.109

Gnomad EAS

AF:

0.0302

Gnomad SAS

AF:

0.124

Gnomad FIN

AF:

0.0745

Gnomad MID

AF:

0.0854

Gnomad NFE

AF:

0.103

Gnomad OTH

AF:

0.0880

GnomAD3 exomes

AF:

0.0935

AC:

23288

AN:

249116

Hom.:

1257

AF XY:

0.0964

AC XY:

13024

AN XY:

135130

show subpopulations

Gnomad AFR exome

AF:

0.138

Gnomad AMR exome

AF:

0.0450

Gnomad ASJ exome

AF:

0.108

Gnomad EAS exome

AF:

0.0330

Gnomad SAS exome

AF:

0.133

Gnomad FIN exome

AF:

0.0831

Gnomad NFE exome

AF:

0.101

Gnomad OTH exome

AF:

0.0965

GnomAD4 exome

AF:

0.0995

AC:

145090

AN:

1458092

Hom.:

7727

Cov.:

AF XY:

0.100

AC XY:

72804

AN XY:

725546

show subpopulations

Gnomad4 AFR exome

AF:

0.143

Gnomad4 AMR exome

AF:

0.0462

Gnomad4 ASJ exome

AF:

0.106

Gnomad4 EAS exome

AF:

0.0419

Gnomad4 SAS exome

AF:

0.127

Gnomad4 FIN exome

AF:

0.0834

Gnomad4 NFE exome

AF:

0.101

Gnomad4 OTH exome

AF:

0.102

GnomAD4 genome

AF:

0.105

AC:

16054

AN:

152212

Hom.:

995

Cov.:

AF XY:

0.102

AC XY:

7587

AN XY:

74422

show subpopulations

Gnomad4 AFR

AF:

0.141

Gnomad4 AMR

AF:

0.0642

Gnomad4 ASJ

AF:

0.109

Gnomad4 EAS

AF:

0.0303

Gnomad4 SAS

AF:

0.124

Gnomad4 FIN

AF:

0.0745

Gnomad4 NFE

AF:

0.103

Gnomad4 OTH

AF:

0.0908

Alfa

AF:

0.100

Hom.:

1097

Bravo

AF:

0.103

Asia WGS

AF:

0.115

AC:

399

AN:

3478

EpiCase

AF:

0.0981

EpiControl

AF:

0.101

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified

Benign:1

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Retinal cone dystrophy 4

Benign:1

Jan 12, 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.69

CADD

Benign

0.95

DANN

Benign

0.54

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over