rs60945277

Positions:

chr12-1879852-T-C

Variant summary

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

The NM_172364.5(CACNA2D4):c.1515A>G(p.Thr505Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.132 in 1,600,736 control chromosomes in the GnomAD database, including 20,033 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.22 ( 5998 hom., cov: 33)

Exomes 𝑓: 0.12 ( 14035 hom. )

Consequence

CACNA2D4
NM_172364.5 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: -0.108

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:

CACNA2D4 (HGNC:):

CACNA2D4 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.65).

BP6

Variant 12-1879852-T-C is Benign according to our data. Variant chr12-1879852-T-C is described in ClinVar as [Benign]. Clinvar id is 262809.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.108 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.495 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA2D4	NM_172364.5 linkuse as main transcript	c.1515A>G	p.Thr505Thr	synonymous_variant	14/38	ENST00000382722.10	NP_758952.4	Q7Z3S7-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
CACNA2D4	ENST00000382722.10 linkuse as main transcript	c.1515A>G	p.Thr505Thr	synonymous_variant	14/38	1	NM_172364.5	ENSP00000372169.4	Q7Z3S7-1
CACNA2D4	ENST00000586184.5 linkuse as main transcript	c.1515A>G	p.Thr505Thr	synonymous_variant	14/37	5		ENSP00000465060.1	Q7Z3S7-5
CACNA2D4	ENST00000587995.5 linkuse as main transcript	c.1515A>G	p.Thr505Thr	synonymous_variant	14/37	5		ENSP00000465372.1	K7EJY1
CACNA2D4	ENST00000585708.5 linkuse as main transcript	c.1323A>G	p.Thr441Thr	synonymous_variant	14/37	5		ENSP00000467697.1	Q7Z3S7-6
CACNA2D4	ENST00000588077.5 linkuse as main transcript	c.1323A>G	p.Thr441Thr	synonymous_variant	14/38	5		ENSP00000468530.1	Q7Z3S7-4
CACNA2D4	ENST00000444595.6 linkuse as main transcript	n.1515A>G		non_coding_transcript_exon_variant	14/37	1		ENSP00000403371.2	E7EUE0

Frequencies

GnomAD3 genomes

AF:

0.217

AC:

33035

AN:

151996

Hom.:

5967

Cov.:

show subpopulations

Gnomad AFR

AF:

0.500

Gnomad AMI

AF:

0.0626

Gnomad AMR

AF:

0.112

Gnomad ASJ

AF:

0.129

Gnomad EAS

AF:

0.0348

Gnomad SAS

AF:

0.169

Gnomad FIN

AF:

0.0850

Gnomad MID

AF:

0.127

Gnomad NFE

AF:

0.115

Gnomad OTH

AF:

0.169

GnomAD3 exomes

AF:

0.128

AC:

29090

AN:

226974

Hom.:

2953

AF XY:

0.126

AC XY:

15443

AN XY:

122650

show subpopulations

Gnomad AFR exome

AF:

0.502

Gnomad AMR exome

AF:

0.0671

Gnomad ASJ exome

AF:

0.127

Gnomad EAS exome

AF:

0.0332

Gnomad SAS exome

AF:

0.175

Gnomad FIN exome

AF:

0.0922

Gnomad NFE exome

AF:

0.111

Gnomad OTH exome

AF:

0.118

GnomAD4 exome

AF:

0.122

AC:

177390

AN:

1448620

Hom.:

14035

Cov.:

AF XY:

0.122

AC XY:

88086

AN XY:

719096

show subpopulations

Gnomad4 AFR exome

AF:

0.510

Gnomad4 AMR exome

AF:

0.0708

Gnomad4 ASJ exome

AF:

0.127

Gnomad4 EAS exome

AF:

0.0561

Gnomad4 SAS exome

AF:

0.167

Gnomad4 FIN exome

AF:

0.0924

Gnomad4 NFE exome

AF:

0.112

Gnomad4 OTH exome

AF:

0.137

GnomAD4 genome

AF:

0.218

AC:

33115

AN:

152116

Hom.:

5998

Cov.:

AF XY:

0.212

AC XY:

15766

AN XY:

74358

show subpopulations

Gnomad4 AFR

AF:

0.500

Gnomad4 AMR

AF:

0.112

Gnomad4 ASJ

AF:

0.129

Gnomad4 EAS

AF:

0.0347

Gnomad4 SAS

AF:

0.170

Gnomad4 FIN

AF:

0.0850

Gnomad4 NFE

AF:

0.115

Gnomad4 OTH

AF:

0.171

Alfa

AF:

0.165

Hom.:

1453

Bravo

AF:

0.228

Asia WGS

AF:

0.166

AC:

577

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

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)	May 26, 2016	- -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

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

BayesDel_noAF

Benign

-0.65

CADD

Benign

1.4

DANN

Benign

0.28

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

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