Genetic Variant NM_000722.4:c.294+7711T>C (chr7-82327424-A-G) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_000722.4(CACNA2D1):c.294+7711T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.553 in 152,068 control chromosomes in the GnomAD database, including 23,935 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.55 ( 23935 hom., cov: 33)

Consequence

CACNA2D1
NM_000722.4 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.546

Publications

3 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:

LOC107986813 (HGNC:):

LOC107986813 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.9).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.691 is higher than 0.05.

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

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
CACNA2D1	NM_000722.4	MANE Select	c.294+7711T>C	intron	N/A	NP_000713.2	P54289-2
CACNA2D1	NM_001366867.1		c.294+7711T>C	intron	N/A	NP_001353796.1	P54289-1
CACNA2D1	NM_001302890.2		c.294+7711T>C	intron	N/A	NP_001289819.1	E7ERK3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
CACNA2D1	ENST00000356860.8	TSL:1 MANE Select	c.294+7711T>C	intron	N/A	ENSP00000349320.3	P54289-2
CACNA2D1	ENST00000423588.1	TSL:1	c.294+7711T>C	intron	N/A	ENSP00000405395.1	E7ERK3
CACNA2D1	ENST00000443883.2	TSL:5	c.294+7711T>C	intron	N/A	ENSP00000409374.2	H0Y715

Frequencies

GnomAD3 genomes

AF:

0.553

AC:

83981

AN:

151950

Hom.:

23909

Cov.:

show subpopulations

Gnomad AFR

AF:

0.690

Gnomad AMI

AF:

0.612

Gnomad AMR

AF:

0.547

Gnomad ASJ

AF:

0.427

Gnomad EAS

AF:

0.711

Gnomad SAS

AF:

0.461

Gnomad FIN

AF:

0.525

Gnomad MID

AF:

0.503

Gnomad NFE

AF:

0.477

Gnomad OTH

AF:

0.507

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome

AF:

0.553

AC:

84062

AN:

152068

Hom.:

23935

Cov.:

AF XY:

0.552

AC XY:

41016

AN XY:

74326

show subpopulations

African (AFR)

AF:

0.690

AC:

28612

AN:

41490

American (AMR)

AF:

0.547

AC:

8358

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.427

AC:

1482

AN:

3470

East Asian (EAS)

AF:

0.711

AC:

3672

AN:

5168

South Asian (SAS)

AF:

0.460

AC:

2215

AN:

4810

European-Finnish (FIN)

AF:

0.525

AC:

5543

AN:

10562

Middle Eastern (MID)

AF:

0.510

AC:

150

AN:

294

European-Non Finnish (NFE)

AF:

0.477

AC:

32405

AN:

67976

Other (OTH)

AF:

0.506

AC:

1068

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1922

3844

5767

7689

9611

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

716

1432

2148

2864

3580

<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:

0.494

Hom.:

9915

Bravo

AF:

0.562

Asia WGS

AF:

0.574

AC:

1995

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.90

CADD

Benign

3.5

(source)

DANN

Benign

0.63

PhyloP100

0.55

Mutation Taster

=100/0

polymorphism (auto)

(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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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over