9-137984918-C-A

Variant names:

• chr9-137984918-C-A
• rs7870040
• NM_000718.4:c.1769+668C>A

Variant summary

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

The NM_000718.4(CACNA1B):​c.1769+668C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.275 in 152,150 control chromosomes in the GnomAD database, including 7,977 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 0.27 (7977 hom., cov: 33)
• Consequence: CACNA1B NM_000718.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.00600
• Publications: 2 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=-0.82).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.625 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1B	NM_000718.4	c.1769+668C>A		intron_variant	Intron 13 of 46	ENST00000371372.6	NP_000709.1
CACNA1B	NM_001243812.2	c.1769+668C>A		intron_variant	Intron 13 of 46		NP_001230741.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1B	ENST00000371372.6	c.1769+668C>A		intron_variant	Intron 13 of 46	5	NM_000718.4	ENSP00000360423.1
CACNA1B	ENST00000371357.5	c.1772+668C>A		intron_variant	Intron 13 of 45	5		ENSP00000360408.1
CACNA1B	ENST00000371363.5	c.1769+668C>A		intron_variant	Intron 13 of 45	5		ENSP00000360414.1
CACNA1B	ENST00000277551.6	c.1769+668C>A		intron_variant	Intron 13 of 46	5		ENSP00000277551.2

Frequencies

GnomAD3 genomes AF: 0.274 AC: 41715 AN: 152032 Hom.: 7959 Cov.: 33

Gnomad AFR AF: 0.512

Gnomad AMI AF: 0.127

Gnomad AMR AF: 0.158

Gnomad ASJ AF: 0.142

Gnomad EAS AF: 0.643

Gnomad SAS AF: 0.275

Gnomad FIN AF: 0.137

Gnomad MID AF: 0.155

Gnomad NFE AF: 0.159

Gnomad OTH AF: 0.245

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

GnomAD4 genome AF: 0.275 AC: 41782 AN: 152150 Hom.: 7977 Cov.: 33 AF XY: 0.273 AC XY: 20335 AN XY: 74382

African (AFR) AF: 0.512 AC: 21232 AN: 41486

American (AMR) AF: 0.158 AC: 2416 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.142 AC: 493 AN: 3472

East Asian (EAS) AF: 0.644 AC: 3322 AN: 5162

South Asian (SAS) AF: 0.276 AC: 1330 AN: 4822

European-Finnish (FIN) AF: 0.137 AC: 1448 AN: 10606

Middle Eastern (MID) AF: 0.156 AC: 46 AN: 294

European-Non Finnish (NFE) AF: 0.159 AC: 10844 AN: 67996

Other (OTH) AF: 0.254 AC: 535 AN: 2110

Alfa AF: 0.188 Hom.: 1976

Bravo AF: 0.286

Asia WGS AF: 0.454 AC: 1582 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	6.6
DANN	Benign	0.80
PhyloP100		-0.0060
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs7870040; hg19: chr9-140879370;