rs74120235

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBP6_Very_Strong

The NM_201596.3(CACNB2):c.121-4T>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0139 in 1,256,432 control chromosomes in the GnomAD database, including 61 homozygotes. There is a variant allele frequency bias in the population database for this variant (GnomAd4), which may indicate mosaicism or somatic mutations in the reference population data. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.00087 ( 0 hom., cov: 26)

Exomes 𝑓: 0.015 ( 61 hom. )

Consequence

CACNB2
NM_201596.3 splice_region, intron

Scores

Splicing: ADA: 0.00002333

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts U:1B:6

Conservation

PhyloP100: -0.151

Publications

5 publications found

Variant links:

Genes affected

CACNB2 (HGNC:1402): (calcium voltage-gated channel auxiliary subunit beta 2) This gene encodes a subunit of a voltage-dependent calcium channel protein that is a member of the voltage-gated calcium channel superfamily. The gene product was originally identified as an antigen target in Lambert-Eaton myasthenic syndrome, an autoimmune disorder. Mutations in this gene are associated with Brugada syndrome. Alternatively spliced variants encoding different isoforms have been described. [provided by RefSeq, Feb 2013]

CACNB2 Gene-Disease associations (from GenCC):

Brugada syndrome 4
Inheritance: AD, Unknown Classification: LIMITED, NO_KNOWN Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine, Genomics England PanelApp
cardiogenetic disease
Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
hypertrophic cardiomyopathy
Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
short QT syndrome
Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

CACNB2 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=-0.87).

BP6

Variant 10-18150879-T-G is Benign according to our data. Variant chr10-18150879-T-G is described in ClinVar as Benign. ClinVar VariationId is 136644.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_201596.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
CACNB2	NM_201596.3	MANE Select	c.121-4T>G	splice_region intron	N/A	NP_963890.2	Q08289-1
CACNB2	NM_201597.3		c.121-4T>G	splice_region intron	N/A	NP_963891.1	Q08289-8
CACNB2	NM_201571.4		c.37-4T>G	splice_region intron	N/A	NP_963865.2	Q08289-4

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
CACNB2	ENST00000324631.13	TSL:1 MANE Select	c.121-4T>G	splice_region intron	N/A	ENSP00000320025.8	Q08289-1
CACNB2	ENST00000352115.10	TSL:1	c.121-4T>G	splice_region intron	N/A	ENSP00000344474.6	Q08289-8
CACNB2	ENST00000282343.13	TSL:1	c.37-4T>G	splice_region intron	N/A	ENSP00000282343.8	Q08289-4

Frequencies

GnomAD3 genomes

AF:

0.000867

AC:

116

AN:

133848

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000737

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000438

Gnomad ASJ

AF:

0.000611

Gnomad EAS

AF:

0.00155

Gnomad SAS

AF:

0.00191

Gnomad FIN

AF:

0.00177

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000840

Gnomad OTH

AF:

0.00109

GnomAD2 exomes

AF:

0.0470

AC:

9034

AN:

192078

AF XY:

0.0483

show subpopulations

Gnomad AFR exome

AF:

0.0482

Gnomad AMR exome

AF:

0.0118

Gnomad ASJ exome

AF:

0.0376

Gnomad EAS exome

AF:

0.0488

Gnomad FIN exome

AF:

0.0905

Gnomad NFE exome

AF:

0.0536

Gnomad OTH exome

AF:

0.0360

GnomAD4 exome

AF:

0.0155

AC:

17373

AN:

1122508

Hom.:

Cov.:

AF XY:

0.0162

AC XY:

9182

AN XY:

566804

show subpopulations

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

African (AFR)

AF:

0.0139

AC:

336

AN:

24116

American (AMR)

AF:

0.00975

AC:

315

AN:

32310

Ashkenazi Jewish (ASJ)

AF:

0.0200

AC:

423

AN:

21192

East Asian (EAS)

AF:

0.0194

AC:

682

AN:

35088

South Asian (SAS)

AF:

0.0168

AC:

1120

AN:

66800

European-Finnish (FIN)

AF:

0.0417

AC:

1726

AN:

41428

Middle Eastern (MID)

AF:

0.0249

AC:

105

AN:

4216

European-Non Finnish (NFE)

AF:

0.0142

AC:

12111

AN:

849960

Other (OTH)

AF:

0.0117

AC:

555

AN:

47398

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.381

Heterozygous variant carriers

797

1594

2390

3187

3984

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

484

968

1452

1936

2420

<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:

0.000866

AC:

116

AN:

133924

Hom.:

Cov.:

AF XY:

0.000917

AC XY:

AN XY:

64342

show subpopulations

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

African (AFR)

AF:

0.000735

AC:

AN:

35354

American (AMR)

AF:

0.000437

AC:

AN:

13716

Ashkenazi Jewish (ASJ)

AF:

0.000611

AC:

AN:

3274

East Asian (EAS)

AF:

0.00156

AC:

AN:

4500

South Asian (SAS)

AF:

0.00192

AC:

AN:

4176

European-Finnish (FIN)

AF:

0.00177

AC:

AN:

6792

Middle Eastern (MID)

AF:

0.00

AC:

AN:

256

European-Non Finnish (NFE)

AF:

0.000840

AC:

AN:

63128

Other (OTH)

AF:

0.00108

AC:

AN:

1854

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.333

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:

0.0749

Hom.:

216

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

not specified (3)

Short QT Syndrome 5 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.87

CADD

Benign

6.5

(source)

DANN

Benign

0.74

PhyloP100

-0.15

Mutation Taster

=99/1

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000023

dbscSNV1_RF

Benign

0.056

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