rs139608070

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_StrongBP6

The NM_000722.4(CACNA2D1):c.2768C>G(p.Thr923Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000627 in 1,611,950 control chromosomes in the GnomAD database, including 1 homozygotes. 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).

Frequency

Genomes: 𝑓 0.00046 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00064 ( 1 hom. )

Consequence

CACNA2D1
NM_000722.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:3

Conservation

PhyloP100: 9.27

Publications

0 publications found

Variant links:

Genes affected

CACNA2D1 (HGNC:1399): (calcium voltage-gated channel auxiliary subunit alpha2delta 1) The preproprotein encoded by this gene is cleaved into multiple chains that comprise the alpha-2 and delta subunits of the voltage-dependent calcium channel complex. Calcium channels mediate the influx of calcium ions into the cell upon membrane polarization. Mutations in this gene can cause cardiac deficiencies, including Brugada syndrome and short QT syndrome. Alternate splicing results in multiple transcript variants, some of which may lack the delta subunit portion. [provided by RefSeq, Nov 2014]

CACNA2D1 Gene-Disease associations (from GenCC):

short QT syndrome
Inheritance: AD Classification: SUPPORTIVE, NO_KNOWN Submitted by: ClinGen, Orphanet
genetic developmental and epileptic encephalopathy
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
developmental and epileptic encephalopathy 110
Inheritance: AR Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae), G2P
Brugada syndrome
Inheritance: Unknown, AD Classification: LIMITED, NO_KNOWN Submitted by: Genomics England PanelApp, Ambry Genetics
Brugada syndrome 1
Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

CACNA2D1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

BP4

Computational evidence support a benign effect (MetaRNN=0.04178846).

BP6

Variant 7-81964068-G-C is Benign according to our data. Variant chr7-81964068-G-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 518537.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000722.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CACNA2D1	NM_000722.4	MANE Select	c.2768C>G	p.Thr923Ser	missense	Exon 34 of 39	NP_000713.2	P54289-2
	CACNA2D1	NM_001366867.1		c.2804C>G	p.Thr935Ser	missense	Exon 34 of 39	NP_001353796.1	P54289-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CACNA2D1	ENST00000356860.8	TSL:1 MANE Select	c.2768C>G	p.Thr923Ser	missense	Exon 34 of 39	ENSP00000349320.3	P54289-2
CACNA2D1	ENST00000443883.2	TSL:5	c.2804C>G	p.Thr935Ser	missense	Exon 34 of 39	ENSP00000409374.2	H0Y715
CACNA2D1	ENST00000957014.1		c.2789C>G	p.Thr930Ser	missense	Exon 34 of 39	ENSP00000627073.1

Frequencies

GnomAD3 genomes

AF:

0.000461

AC:

AN:

151882

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000266

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00112

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:

0.000603

Gnomad OTH

AF:

0.000480

GnomAD2 exomes

AF:

0.000233

AC:

AN:

249026

AF XY:

0.000252

show subpopulations

Gnomad AFR exome

AF:

0.000127

Gnomad AMR exome

AF:

0.000175

Gnomad ASJ exome

AF:

0.0000998

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000427

Gnomad OTH exome

AF:

0.000166

GnomAD4 exome

AF:

0.000644

AC:

940

AN:

1459950

Hom.:

Cov.:

AF XY:

0.000654

AC XY:

475

AN XY:

726326

show subpopulations

African (AFR)

AF:

0.0000899

AC:

AN:

33384

American (AMR)

AF:

0.000247

AC:

AN:

44560

Ashkenazi Jewish (ASJ)

AF:

0.0000384

AC:

AN:

26068

East Asian (EAS)

AF:

0.00

AC:

AN:

39638

South Asian (SAS)

AF:

0.00

AC:

AN:

86218

European-Finnish (FIN)

AF:

0.0000188

AC:

AN:

53296

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5750

European-Non Finnish (NFE)

AF:

0.000804

AC:

893

AN:

1110794

Other (OTH)

AF:

0.000515

AC:

AN:

60242

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.450

Heterozygous variant carriers

130

173

216

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

120

160

200

<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:

0.000461

AC:

AN:

152000

Hom.:

Cov.:

AF XY:

0.000417

AC XY:

AN XY:

74280

show subpopulations

African (AFR)

AF:

0.000265

AC:

AN:

41502

American (AMR)

AF:

0.00112

AC:

AN:

15220

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5146

South Asian (SAS)

AF:

0.00

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10586

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000603

AC:

AN:

67948

Other (OTH)

AF:

0.000475

AC:

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

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:

0.000736

Hom.:

Bravo

AF:

0.000510

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00105

AC:

ExAC

AF:

0.000206

AC:

EpiCase

AF:

0.000328

EpiControl

AF:

0.000475

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

Brugada syndrome (1)

Cardiovascular phenotype (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.095

BayesDel_addAF

Benign

-0.50

BayesDel_noAF

Benign

-0.59

CADD

Benign

(source)

DANN

Benign

0.43

DEOGEN2

Benign

0.044

Eigen

Benign

-0.23

Eigen_PC

Benign

0.071

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Benign

0.70

M_CAP

Benign

0.0019

MetaRNN

Benign

0.042

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.90

PhyloP100

9.3

PrimateAI

Uncertain

0.51

PROVEAN

Benign

0.20

REVEL

Benign

0.18

Sift

Benign

0.95

Sift4G

Benign

1.0

Polyphen

0.0020

Vest4

0.21

MVP

0.082

MPC

0.42

ClinPred

0.11

GERP RS

5.3

Varity_R

0.11

gMVP

0.39

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

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