rs61741336

Positions:

chr12-1797466-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_172364.5(CACNA2D4):c.3065C>T(p.Pro1022Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00949 in 1,585,220 control chromosomes in the GnomAD database, including 115 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 Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. P1022P) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0066 ( 4 hom., cov: 34)

Exomes 𝑓: 0.0098 ( 111 hom. )

Consequence

CACNA2D4
NM_172364.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 0.634

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0038063228).

BP6

Variant 12-1797466-G-A is Benign according to our data. Variant chr12-1797466-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 196962.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00663 (1010/152312) while in subpopulation SAS AF= 0.0213 (103/4830). AF 95% confidence interval is 0.018. There are 4 homozygotes in gnomad4. There are 477 alleles in male gnomad4 subpopulation. Median coverage is 34. 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
CACNA2D4	NM_172364.5 linkuse as main transcript	c.3065C>T	p.Pro1022Leu	missense_variant	35/38	ENST00000382722.10
CACNA2D4	XM_011521041.3 linkuse as main transcript	c.3002C>T	p.Pro1001Leu	missense_variant	34/36
CACNA2D4	XM_047429897.1 linkuse as main transcript	c.2993C>T	p.Pro998Leu	missense_variant	34/36

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CACNA2D4	ENST00000382722.10 linkuse as main transcript	c.3065C>T	p.Pro1022Leu	missense_variant	35/38	1	NM_172364.5	P2	Q7Z3S7-1

Frequencies

GnomAD3 genomes

AF:

0.00664

AC:

1011

AN:

152194

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00154

Gnomad AMI

AF:

0.0121

Gnomad AMR

AF:

0.00798

Gnomad ASJ

AF:

0.00634

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.0213

Gnomad FIN

AF:

0.000848

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.00972

Gnomad OTH

AF:

0.00718

GnomAD3 exomes

AF:

0.00850

AC:

1756

AN:

206662

Hom.:

AF XY:

0.00950

AC XY:

1069

AN XY:

112514

show subpopulations

Gnomad AFR exome

AF:

0.00175

Gnomad AMR exome

AF:

0.00431

Gnomad ASJ exome

AF:

0.00534

Gnomad EAS exome

AF:

0.000129

Gnomad SAS exome

AF:

0.0233

Gnomad FIN exome

AF:

0.00104

Gnomad NFE exome

AF:

0.00927

Gnomad OTH exome

AF:

0.00904

GnomAD4 exome

AF:

0.00979

AC:

14027

AN:

1432908

Hom.:

111

Cov.:

AF XY:

0.0102

AC XY:

7271

AN XY:

710932

show subpopulations

Gnomad4 AFR exome

AF:

0.00106

Gnomad4 AMR exome

AF:

0.00467

Gnomad4 ASJ exome

AF:

0.00603

Gnomad4 EAS exome

AF:

0.0000521

Gnomad4 SAS exome

AF:

0.0232

Gnomad4 FIN exome

AF:

0.00170

Gnomad4 NFE exome

AF:

0.0101

Gnomad4 OTH exome

AF:

0.00800

GnomAD4 genome

AF:

0.00663

AC:

1010

AN:

152312

Hom.:

Cov.:

AF XY:

0.00641

AC XY:

477

AN XY:

74470

show subpopulations

Gnomad4 AFR

AF:

0.00154

Gnomad4 AMR

AF:

0.00797

Gnomad4 ASJ

AF:

0.00634

Gnomad4 EAS

AF:

0.000194

Gnomad4 SAS

AF:

0.0213

Gnomad4 FIN

AF:

0.000848

Gnomad4 NFE

AF:

0.00970

Gnomad4 OTH

AF:

0.00710

Alfa

AF:

0.00910

Hom.:

Bravo

AF:

0.00659

TwinsUK

AF:

0.0111

AC:

ALSPAC

AF:

0.00804

AC:

ESP6500AA

AF:

0.00177

AC:

ESP6500EA

AF:

0.00967

AC:

ExAC

AF:

0.00730

AC:

874

Asia WGS

AF:

0.00520

AC:

AN:

3478

ClinVar

Significance: Benign/Likely 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	Eurofins Ntd Llc (ga)	Aug 11, 2014	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Retinal cone dystrophy 4

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Dec 09, 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 provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.097

BayesDel_addAF

Benign

-0.46

BayesDel_noAF

Benign

-0.42

CADD

Benign

DANN

Benign

0.95

DEOGEN2

Benign

0.15

T;.;.;.;.;.;.

Eigen

Benign

-1.0

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.19

MetaRNN

Benign

0.0038

T;T;T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.5

M;.;.;.;.;M;.

MutationTaster

Benign

1.0

N;N;N;N;N;N;N

PrimateAI

Benign

0.27

PROVEAN

Uncertain

-2.6

D;D;.;.;.;.;.

REVEL

Benign

0.044

Sift

Benign

0.30

T;T;.;.;.;.;.

Sift4G

Benign

0.30

T;T;T;T;T;T;T

Polyphen

0.084

B;B;.;B;.;.;.

Vest4

0.23

MVP

0.072

MPC

0.14

ClinPred

0.0087

GERP RS

-1.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.048

gMVP

0.50

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