dbSNP rs753131879: CACNA2D2:p.Phe718Phe (chr3-50367892-G-A) – ACMG Classification: Likely_benign (-5 pts)

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 2P and 7B. PM2BP4_StrongBP6_ModerateBP7

The NM_006030.4(CACNA2D2):c.2154C>T(p.Phe718Phe) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000045 in 888,486 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.0000071 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000040 ( 0 hom. )

Consequence

CACNA2D2
NM_006030.4 synonymous

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 2.08

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:

ENSG00000272104 (HGNC:):

ENSG00000272104 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -5 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.5).

BP6

Variant 3-50367892-G-A is Benign according to our data. Variant chr3-50367892-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 461308.Status of the report is criteria_provided_single_submitter, 1 stars.

BP7

Synonymous conserved (PhyloP=2.09 with no splicing effect.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006030.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CACNA2D2	NM_006030.4	MANE Select	c.2154C>T	p.Phe718Phe	synonymous	Exon 25 of 38	NP_006021.2	Q9NY47-2
CACNA2D2	NM_001174051.3		c.2175C>T	p.Phe725Phe	synonymous	Exon 26 of 39	NP_001167522.1	Q9NY47-1
CACNA2D2	NM_001005505.3		c.2154C>T	p.Phe718Phe	synonymous	Exon 25 of 38	NP_001005505.1	Q9NY47-3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CACNA2D2	ENST00000424201.7	TSL:1 MANE Select	c.2154C>T	p.Phe718Phe	synonymous	Exon 25 of 38	ENSP00000390329.2	Q9NY47-2
CACNA2D2	ENST00000423994.6	TSL:5	c.2175C>T	p.Phe725Phe	synonymous	Exon 26 of 39	ENSP00000407393.2	C9JVC9
CACNA2D2	ENST00000479441.1	TSL:1	c.2175C>T	p.Phe725Phe	synonymous	Exon 26 of 39	ENSP00000418081.1	Q9NY47-1

Frequencies

GnomAD3 genomes

AF:

0.00000710

AC:

AN:

140896

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000703

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

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

GnomAD2 exomes

AF:

0.0000162

AC:

AN:

246212

AF XY:

0.0000150

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000585

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000903

Gnomad OTH exome

AF:

0.000166

GnomAD4 exome

AF:

0.00000401

AC:

AN:

747590

Hom.:

Cov.:

AF XY:

0.00000259

AC XY:

AN XY:

386028

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

17502

American (AMR)

AF:

0.0000272

AC:

AN:

36760

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

14150

East Asian (EAS)

AF:

0.00

AC:

AN:

15552

South Asian (SAS)

AF:

0.00

AC:

AN:

73750

European-Finnish (FIN)

AF:

0.00

AC:

AN:

32804

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3606

European-Non Finnish (NFE)

AF:

0.00000381

AC:

AN:

524454

Other (OTH)

AF:

0.00

AC:

AN:

29012

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0136242), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.392

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00000710

AC:

AN:

140896

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

68244

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

39310

American (AMR)

AF:

0.0000703

AC:

AN:

14224

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3308

East Asian (EAS)

AF:

0.00

AC:

AN:

3954

South Asian (SAS)

AF:

0.00

AC:

AN:

3834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

8766

Middle Eastern (MID)

AF:

0.00

AC:

AN:

308

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

64350

Other (OTH)

AF:

0.00

AC:

AN:

1982

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

ClinVar

ClinVar submissions

Significance:Likely benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Developmental and epileptic encephalopathy (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.50

CADD

Benign

(source)

DANN

Benign

0.58

PhyloP100

2.1

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over