Genetic Variant NM_000718.4:c.30C>T (chr9-137877963-C-T) – ACMG Classification: Benign (-17 pts)

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP4_StrongBP6_Very_StrongBP7BS1

The NM_000718.4(CACNA1B):c.30C>T(p.Gly10Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00433 in 1,101,120 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 0.0031 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0045 ( 1 hom. )

Consequence

CACNA1B
NM_000718.4 synonymous

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 1.66

Publications

2 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 -17 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.51).

BP6

Variant 9-137877963-C-T is Benign according to our data. Variant chr9-137877963-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 374676.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=1.65 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00315 (468/148754) while in subpopulation NFE AF = 0.0048 (320/66674). AF 95% confidence interval is 0.00437. There are 0 homozygotes in GnomAd4. There are 202 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.30C>T	p.Gly10Gly	synonymous	Exon 1 of 47	NP_000709.1	Q00975-1
CACNA1B	NM_001243812.2		c.30C>T	p.Gly10Gly	synonymous	Exon 1 of 47	NP_001230741.1	Q00975-2
CACNA1B-AS2	NR_121583.1		n.2692-2283G>A		intron	N/A

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CACNA1B	ENST00000371372.6	TSL:5 MANE Select	c.30C>T	p.Gly10Gly	synonymous	Exon 1 of 47	ENSP00000360423.1	Q00975-1
CACNA1B	ENST00000371357.5	TSL:5	c.30C>T	p.Gly10Gly	synonymous	Exon 1 of 46	ENSP00000360408.1	B1AQK7
CACNA1B	ENST00000371363.5	TSL:5	c.30C>T	p.Gly10Gly	synonymous	Exon 1 of 46	ENSP00000360414.1	B1AQK6

Frequencies

GnomAD3 genomes

AF:

0.00317

AC:

471

AN:

148652

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00115

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00481

Gnomad ASJ

AF:

0.00117

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00352

Gnomad FIN

AF:

0.000213

Gnomad MID

AF:

0.00641

Gnomad NFE

AF:

0.00481

Gnomad OTH

AF:

0.00293

GnomAD2 exomes

AF:

0.000951

AC:

AN:

7364

AF XY:

0.00162

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:

0.00

Gnomad NFE exome

AF:

0.00419

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00451

AC:

4298

AN:

952366

Hom.:

Cov.:

AF XY:

0.00445

AC XY:

1992

AN XY:

448050

show subpopulations

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

African (AFR)

AF:

0.00114

AC:

AN:

18382

American (AMR)

AF:

0.00921

AC:

AN:

4778

Ashkenazi Jewish (ASJ)

AF:

0.00184

AC:

AN:

9216

East Asian (EAS)

AF:

0.00

AC:

AN:

11212

South Asian (SAS)

AF:

0.00389

AC:

AN:

18260

European-Finnish (FIN)

AF:

0.000930

AC:

AN:

16132

Middle Eastern (MID)

AF:

0.00844

AC:

AN:

2250

European-Non Finnish (NFE)

AF:

0.00475

AC:

3979

AN:

837404

Other (OTH)

AF:

0.00380

AC:

132

AN:

34732

⚠️ 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: 0.385

Heterozygous variant carriers

184

368

552

736

920

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

204

408

612

816

1020

<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:

0.00315

AC:

468

AN:

148754

Hom.:

Cov.:

AF XY:

0.00278

AC XY:

202

AN XY:

72534

show subpopulations

African (AFR)

AF:

0.00114

AC:

AN:

41136

American (AMR)

AF:

0.00467

AC:

AN:

15000

Ashkenazi Jewish (ASJ)

AF:

0.00117

AC:

AN:

3420

East Asian (EAS)

AF:

0.00

AC:

AN:

5066

South Asian (SAS)

AF:

0.00353

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.000213

AC:

AN:

9368

Middle Eastern (MID)

AF:

0.00690

AC:

AN:

290

European-Non Finnish (NFE)

AF:

0.00480

AC:

320

AN:

66674

Other (OTH)

AF:

0.00290

AC:

AN:

2068

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.446

Heterozygous variant carriers

122

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:

0.00300

Hom.:

ClinVar

ClinVar submissions

Significance:Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (5)

CACNA1B-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.51

CADD

Benign

(source)

DANN

Benign

0.95

PhyloP100

1.7

PromoterAI

-0.086

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