rs1317078806

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_ModerateBP6BS1

The NM_006030.4(CACNA2D2):c.17G>C(p.Arg6Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000204 in 146,866 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R6W) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

CACNA2D2
NM_006030.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:1

Conservation

PhyloP100: -0.797

Publications

0 publications found

Variant links:

Genes affected

CACNA2D2 (HGNC:1400): (calcium voltage-gated channel auxiliary subunit alpha2delta 2) Calcium channels mediate the entry of calcium ions into the cell upon membrane polarization. This gene encodes the alpha-2/delta subunit of the voltage-dependent calcium channel complex. The complex consists of the main channel-forming subunit alpha-1, and auxiliary subunits alpha-2/delta, beta, and gamma. The auxiliary subunits function in the assembly and membrane localization of the complex, and modulate calcium currents and channel activation/inactivation kinetics. The subunit encoded by this gene undergoes post-translational cleavage to yield the extracellular alpha2 peptide and a membrane-anchored delta polypeptide. This subunit is a receptor for the antiepileptic drug, gabapentin. Mutations in this gene are associated with early infantile epileptic encephalopathy. Single nucleotide polymorphisms in this gene are correlated with increased sensitivity to opioid drugs. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Mar 2014]

CACNA2D2 Gene-Disease associations (from GenCC):

cerebellar atrophy with seizures and variable developmental delay
Inheritance: AR Classification: STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
complex neurodevelopmental disorder
Inheritance: AR Classification: MODERATE Submitted by: ClinGen

CACNA2D2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -7 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.09705219).

BP6

Variant 3-50503407-C-G is Benign according to our data. Variant chr3-50503407-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 461303.We mark this variant Likely_benign, oryginal submission is: [Conflicting_classifications_of_pathogenicity].

BS1

Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000204 (30/146866) while in subpopulation EAS AF = 0.000809 (4/4942). AF 95% confidence interval is 0.000431. There are 0 homozygotes in GnomAd4. There are 14 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA2D2	NM_006030.4 link	c.17G>C	p.Arg6Pro	missense_variant	Exon 1 of 38	ENST00000424201.7	NP_006021.2	Q9NY47-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
CACNA2D2	ENST00000424201.7 link	c.17G>C	p.Arg6Pro	missense_variant	Exon 1 of 38	1	NM_006030.4	ENSP00000390329.2	Q9NY47-2
CACNA2D2	ENST00000423994.6 link	c.17G>C	p.Arg6Pro	missense_variant	Exon 1 of 39	5		ENSP00000407393.2	C9JVC9
CACNA2D2	ENST00000266039.7 link	c.17G>C	p.Arg6Pro	missense_variant	Exon 1 of 38	1		ENSP00000266039.3	Q9NY47-3
CACNA2D2	ENST00000360963.7 link	c.-2+662G>C		intron_variant	Intron 1 of 37	1		ENSP00000354228.3	Q9NY47-4

Frequencies

GnomAD3 genomes

AF:

0.000204

AC:

AN:

146776

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000622

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000676

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000806

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

71468

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

38268

African (AFR)

AF:

0.00

AC:

AN:

1620

American (AMR)

AF:

0.00

AC:

AN:

2264

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2090

East Asian (EAS)

AF:

0.00

AC:

AN:

4204

South Asian (SAS)

AF:

0.00

AC:

AN:

1516

European-Finnish (FIN)

AF:

0.00

AC:

AN:

7640

Middle Eastern (MID)

AF:

0.00

AC:

AN:

346

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

47392

Other (OTH)

AF:

0.00

AC:

AN:

4396

GnomAD4 genome

AF:

0.000204

AC:

AN:

146866

Hom.:

Cov.:

AF XY:

0.000196

AC XY:

AN XY:

71518

show subpopulations

African (AFR)

AF:

0.000621

AC:

AN:

40290

American (AMR)

AF:

0.0000675

AC:

AN:

14820

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3408

East Asian (EAS)

AF:

0.000809

AC:

AN:

4942

South Asian (SAS)

AF:

0.00

AC:

AN:

4742

European-Finnish (FIN)

AF:

0.00

AC:

AN:

9022

Middle Eastern (MID)

AF:

0.00

AC:

AN:

290

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

66386

Other (OTH)

AF:

0.00

AC:

AN:

2056

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.000174

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Developmental and epileptic encephalopathy

Uncertain:1

Dec 21, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces arginine, which is basic and polar, with proline, which is neutral and non-polar, at codon 6 of the CACNA2D2 protein (p.Arg6Pro). This variant is present in population databases (no rsID available, gnomAD 0.2%). This variant has not been reported in the literature in individuals affected with CACNA2D2-related conditions. ClinVar contains an entry for this variant (Variation ID: 461303). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Cerebellar atrophy with seizures and variable developmental delay

Benign:1

Sep 20, 2024

3billion

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The homozygous variant was found in patients diagnosed with another variant in a different gene, with no symptoms related to the gene containing the homozygous variant. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.091

BayesDel_addAF

Benign

-0.53

BayesDel_noAF

Benign

-0.63

CADD

Benign

(source)

DANN

Benign

0.90

DEOGEN2

Benign

0.0073

.;T;.;.;T

Eigen

Benign

-0.92

Eigen_PC

Benign

-0.93

FATHMM_MKL

Benign

0.15

LIST_S2

Benign

0.74

T;T;T;T;T

M_CAP

Pathogenic

0.30

MetaRNN

Benign

0.097

T;T;T;T;T

MetaSVM

Benign

-0.95

MutationAssessor

Benign

1.1

.;.;L;L;L

PhyloP100

-0.80

PrimateAI

Pathogenic

0.88

PROVEAN

Benign

-0.45

N;N;N;N;N

REVEL

Benign

0.040

Sift

Benign

0.056

T;T;T;T;D

Sift4G

Benign

0.25

T;T;T;T;T

Polyphen

0.0

.;.;.;B;B

Vest4

0.21

MutPred

0.30

Loss of MoRF binding (P = 0);Loss of MoRF binding (P = 0);Loss of MoRF binding (P = 0);Loss of MoRF binding (P = 0);Loss of MoRF binding (P = 0);

MVP

0.068

MPC

0.24

ClinPred

0.097

GERP RS

-3.4

PromoterAI

0.060

Neutral

(source)

Varity_R

0.19

gMVP

0.41

Mutation Taster

=82/18

polymorphism

(source)

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

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rs1317078806

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over