Genetic Variant CACNA1B:p.Asp6Asp (chr9-137877951-C-T) – ACMG Classification: Benign (-15 pts)

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 0P and 15B. BP4_ModerateBP6_Very_StrongBP7BS1

The NM_000718.4(CACNA1B):c.18C>T(p.Asp6Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00278 in 148,052 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0028 ( 1 hom., cov: 33)

Exomes 𝑓: 0.0024 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

CACNA1B
NM_000718.4 synonymous

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 0.732

Publications

0 publications found

Variant links:

Genes affected

CACNA1B (HGNC:1389): (calcium voltage-gated channel subunit alpha1 B) The protein encoded by this gene is the pore-forming subunit of an N-type voltage-dependent calcium channel, which controls neurotransmitter release from neurons. The encoded protein forms a complex with alpha-2, beta, and delta subunits to form the high-voltage activated channel. This channel is sensitive to omega-conotoxin-GVIA and omega-agatoxin-IIIA but insensitive to dihydropyridines. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Aug 2011]

CACNA1B Gene-Disease associations (from GenCC):

neurodevelopmental disorder with seizures and nonepileptic hyperkinetic movements
Inheritance: AR Classification: STRONG, MODERATE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P, Illumina
complex neurodevelopmental disorder with motor features
Inheritance: AR Classification: MODERATE Submitted by: ClinGen
undetermined early-onset epileptic encephalopathy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

CACNA1B links:

CACNA1B-AS2 (HGNC:58213):

CACNA1B-AS2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -15 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.4).

BP6

Variant 9-137877951-C-T is Benign according to our data. Variant chr9-137877951-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 1321510.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.732 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00278 (411/148052) while in subpopulation NFE AF = 0.00408 (271/66490). AF 95% confidence interval is 0.00368. There are 1 homozygotes in GnomAd4. There are 208 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000718.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CACNA1B	NM_000718.4	MANE Select	c.18C>T	p.Asp6Asp	synonymous	Exon 1 of 47	NP_000709.1	Q00975-1
CACNA1B	NM_001243812.2		c.18C>T	p.Asp6Asp	synonymous	Exon 1 of 47	NP_001230741.1	Q00975-2
CACNA1B-AS2	NR_121583.1		n.2692-2271G>A		intron	N/A

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CACNA1B	ENST00000371372.6	TSL:5 MANE Select	c.18C>T	p.Asp6Asp	synonymous	Exon 1 of 47	ENSP00000360423.1	Q00975-1
CACNA1B	ENST00000371357.5	TSL:5	c.18C>T	p.Asp6Asp	synonymous	Exon 1 of 46	ENSP00000360408.1	B1AQK7
CACNA1B	ENST00000371363.5	TSL:5	c.18C>T	p.Asp6Asp	synonymous	Exon 1 of 46	ENSP00000360414.1	B1AQK6

Frequencies

GnomAD3 genomes

AF:

0.00278

AC:

411

AN:

147952

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000490

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00242

Gnomad ASJ

AF:

0.00205

Gnomad EAS

AF:

0.000200

Gnomad SAS

AF:

0.00187

Gnomad FIN

AF:

0.00583

Gnomad MID

AF:

0.0132

Gnomad NFE

AF:

0.00408

Gnomad OTH

AF:

0.00442

GnomAD2 exomes

AF:

0.00416

AC:

AN:

4564

AF XY:

0.00426

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00499

Gnomad NFE exome

AF:

0.00234

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00237

AC:

2201

AN:

929218

Hom.:

Cov.:

AF XY:

0.00236

AC XY:

1029

AN XY:

436632

show subpopulations

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

African (AFR)

AF:

0.000502

AC:

AN:

17934

American (AMR)

AF:

0.00183

AC:

AN:

4366

Ashkenazi Jewish (ASJ)

AF:

0.00185

AC:

AN:

8650

East Asian (EAS)

AF:

0.00

AC:

AN:

9510

South Asian (SAS)

AF:

0.00233

AC:

AN:

18014

European-Finnish (FIN)

AF:

0.00501

AC:

AN:

13168

Middle Eastern (MID)

AF:

0.00556

AC:

AN:

2160

European-Non Finnish (NFE)

AF:

0.00241

AC:

1979

AN:

821854

Other (OTH)

AF:

0.00206

AC:

AN:

33562

⚠️ 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: 0.400

Heterozygous variant carriers

186

279

372

465

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

180

270

360

450

<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:

0.00278

AC:

411

AN:

148052

Hom.:

Cov.:

AF XY:

0.00288

AC XY:

208

AN XY:

72166

show subpopulations

African (AFR)

AF:

0.000488

AC:

AN:

40946

American (AMR)

AF:

0.00241

AC:

AN:

14916

Ashkenazi Jewish (ASJ)

AF:

0.00205

AC:

AN:

3408

East Asian (EAS)

AF:

0.000200

AC:

AN:

4988

South Asian (SAS)

AF:

0.00188

AC:

AN:

4798

European-Finnish (FIN)

AF:

0.00583

AC:

AN:

9258

Middle Eastern (MID)

AF:

0.0142

AC:

AN:

282

European-Non Finnish (NFE)

AF:

0.00408

AC:

271

AN:

66490

Other (OTH)

AF:

0.00436

AC:

AN:

2062

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.456

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:

0.00282

Hom.:

Bravo

AF:

0.00247

ClinVar

ClinVar submissions

Significance:Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

CACNA1B-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.40

CADD

Benign

(source)

DANN

Benign

0.97

PhyloP100

0.73

PromoterAI

-0.064

Neutral

(source)

Mutation Taster

=296/4

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