9-138076863-T-C

Variant names:

• chr9-138076863-T-C
• rs936249
• NM_000718.4:c.4949+953T>C

Variant summary

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

The NM_000718.4(CACNA1B):​c.4949+953T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.867 in 152,204 control chromosomes in the GnomAD database, including 58,213 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 0.87 (58213 hom., cov: 33)
• Consequence: CACNA1B NM_000718.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0240
• Publications: 4 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: Illumina, Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
• 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=-0.88).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.943 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1B	NM_000718.4	c.4949+953T>C		intron_variant	Intron 35 of 46	ENST00000371372.6	NP_000709.1
CACNA1B	NM_001243812.2	c.4949+953T>C		intron_variant	Intron 35 of 46		NP_001230741.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1B	ENST00000371372.6	c.4949+953T>C		intron_variant	Intron 35 of 46	5	NM_000718.4	ENSP00000360423.1
CACNA1B	ENST00000371357.5	c.4946+953T>C		intron_variant	Intron 34 of 45	5		ENSP00000360408.1
CACNA1B	ENST00000371363.5	c.4943+953T>C		intron_variant	Intron 34 of 45	5		ENSP00000360414.1
CACNA1B	ENST00000277551.6	c.4949+953T>C		intron_variant	Intron 35 of 46	5		ENSP00000277551.2

Frequencies

GnomAD3 genomes AF: 0.868 AC: 131953 AN: 152086 Hom.: 58195 Cov.: 33

Gnomad AFR AF: 0.704

Gnomad AMI AF: 0.939

Gnomad AMR AF: 0.889

Gnomad ASJ AF: 0.953

Gnomad EAS AF: 0.765

Gnomad SAS AF: 0.908

Gnomad FIN AF: 0.944

Gnomad MID AF: 0.934

Gnomad NFE AF: 0.949

Gnomad OTH AF: 0.899

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

GnomAD4 genome AF: 0.867 AC: 132022 AN: 152204 Hom.: 58213 Cov.: 33 AF XY: 0.869 AC XY: 64627 AN XY: 74412

African (AFR) AF: 0.703 AC: 29188 AN: 41492

American (AMR) AF: 0.889 AC: 13596 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.953 AC: 3310 AN: 3472

East Asian (EAS) AF: 0.765 AC: 3949 AN: 5160

South Asian (SAS) AF: 0.908 AC: 4374 AN: 4818

European-Finnish (FIN) AF: 0.944 AC: 10026 AN: 10620

Middle Eastern (MID) AF: 0.929 AC: 273 AN: 294

European-Non Finnish (NFE) AF: 0.949 AC: 64555 AN: 68024

Other (OTH) AF: 0.897 AC: 1895 AN: 2112

Alfa AF: 0.922 Hom.: 108671

Bravo AF: 0.857

Asia WGS AF: 0.838 AC: 2915 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	1.6
DANN	Benign	0.63
PhyloP100		-0.024
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: rs936249; hg19: chr9-140971315; COSMIC: COSV53150877;