rs1291849966

Variant names:

• chr9-137877927-G-T
• rs1291849966
• NM_000718.4:c.-7G>T

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP6

The NM_000718.4(CACNA1B):​c.-7G>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000135 in 148,022 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.000014 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CACNA1B NM_000718.4 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Likely benign no assertion criteria provided B:1
• Conservation: PhyloP100: -0.0190
• Publications: 0 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

CACNA1B-AS2 (HGNC:58213):

ACMG classification

Our verdict: Likely_benign. The variant received -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.48).
• BP6: Variant 9-137877927-G-T is Benign according to our data. Variant chr9-137877927-G-T is described in ClinVar as Likely_benign. ClinVar VariationId is 3029672.Status of the report is no_assertion_criteria_provided, 0 stars.

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.-7G>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 47	NP_000709.1	Q00975-1
	CACNA1B	NM_000718.4	MANE Select	c.-7G>T		5_prime_UTR	Exon 1 of 47	NP_000709.1	Q00975-1
	CACNA1B	NM_001243812.2		c.-7G>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 47	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.-7G>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 47	ENSP00000360423.1	Q00975-1
	CACNA1B	ENST00000371363.5	TSL:5	c.-7G>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 46	ENSP00000360414.1	B1AQK6
	CACNA1B	ENST00000277551.6	TSL:5	c.-7G>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 47	ENSP00000277551.2	Q00975-2

Frequencies

GnomAD3 genomes AF: 0.0000135 AC: 2 AN: 148022 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000487

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 899066 Hom.: 0 Cov.: 18 AF XY: 0.00 AC XY: 0 AN XY: 421306

African (AFR) AF: 0.00 AC: 0 AN: 17076

American (AMR) AF: 0.00 AC: 0 AN: 3676

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 7718

East Asian (EAS) AF: 0.00 AC: 0 AN: 7178

South Asian (SAS) AF: 0.00 AC: 0 AN: 17718

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9754

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1998

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 802156

Other (OTH) AF: 0.00 AC: 0 AN: 31792

GnomAD4 genome AF: 0.0000135 AC: 2 AN: 148022 Hom.: 0 Cov.: 33 AF XY: 0.0000139 AC XY: 1 AN XY: 72070

African (AFR) AF: 0.0000487 AC: 2 AN: 41038

American (AMR) AF: 0.00 AC: 0 AN: 14908

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3402

East Asian (EAS) AF: 0.00 AC: 0 AN: 5076

South Asian (SAS) AF: 0.00 AC: 0 AN: 4814

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9140

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 310

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 66388

Other (OTH) AF: 0.00 AC: 0 AN: 2042

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000151

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	1	CACNA1B-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.48
CADD	Benign	15
DANN	Benign	0.92
PhyloP100		-0.019
PromoterAI		-0.0045	Neutral

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: rs1291849966; hg19: chr9-140772379;