9-138109494-G-T

Variant names:

• chr9-138109494-G-T
• rs7357733
• NM_000718.4:c.5429-2904G>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000718.4(CACNA1B):​c.5429-2904G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.52 in 152,038 control chromosomes in the GnomAD database, including 22,224 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 0.52 (22224 hom., cov: 33)
• Consequence: CACNA1B NM_000718.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.26
• Publications: 8 publications found

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

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.99).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.726 is higher than 0.05.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CACNA1B	NM_000718.4	MANE Select	c.5429-2904G>T		intron	N/A	NP_000709.1	Q00975-1
	CACNA1B	NM_001243812.2		c.5429-2904G>T		intron	N/A	NP_001230741.1	Q00975-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CACNA1B	ENST00000371372.6	TSL:5 MANE Select	c.5429-2904G>T		intron	N/A	ENSP00000360423.1	Q00975-1
	CACNA1B	ENST00000371357.5	TSL:5	c.5426-2904G>T		intron	N/A	ENSP00000360408.1	B1AQK7
	CACNA1B	ENST00000371363.5	TSL:5	c.5423-2904G>T		intron	N/A	ENSP00000360414.1	B1AQK6

Frequencies

GnomAD3 genomes AF: 0.520 AC: 79038 AN: 151920 Hom.: 22175 Cov.: 33

Gnomad AFR AF: 0.733

Gnomad AMI AF: 0.532

Gnomad AMR AF: 0.385

Gnomad ASJ AF: 0.539

Gnomad EAS AF: 0.541

Gnomad SAS AF: 0.462

Gnomad FIN AF: 0.326

Gnomad MID AF: 0.592

Gnomad NFE AF: 0.452

Gnomad OTH AF: 0.534

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

GnomAD4 genome AF: 0.520 AC: 79135 AN: 152038 Hom.: 22224 Cov.: 33 AF XY: 0.511 AC XY: 37968 AN XY: 74306

African (AFR) AF: 0.733 AC: 30402 AN: 41454

American (AMR) AF: 0.385 AC: 5877 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.539 AC: 1870 AN: 3468

East Asian (EAS) AF: 0.542 AC: 2788 AN: 5148

South Asian (SAS) AF: 0.463 AC: 2230 AN: 4816

European-Finnish (FIN) AF: 0.326 AC: 3454 AN: 10592

Middle Eastern (MID) AF: 0.592 AC: 174 AN: 294

European-Non Finnish (NFE) AF: 0.452 AC: 30718 AN: 67970

Other (OTH) AF: 0.539 AC: 1138 AN: 2110

Alfa AF: 0.477 Hom.: 69197

Bravo AF: 0.537

Asia WGS AF: 0.539 AC: 1878 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.99
CADD	Benign	1.7
DANN	Benign	0.40
PhyloP100		-2.3
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs7357733; hg19: chr9-141003946;