9-137878161-C-T

Variant names:

• chr9-137878161-C-T
• rs139719558
• NM_000718.4:c.228C>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000718.4(CACNA1B):​c.228C>T​(p.Phe76Phe) variant causes a synonymous change. The variant was absent in control chromosomes in GnomAD project. 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: not found (cov: 34)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CACNA1B NM_000718.4 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.04
• Publications: 7 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.26).

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.228C>T	p.Phe76Phe	synonymous	Exon 1 of 47	NP_000709.1	Q00975-1
	CACNA1B	NM_001243812.2		c.228C>T	p.Phe76Phe	synonymous	Exon 1 of 47	NP_001230741.1	Q00975-2
	CACNA1B-AS2	NR_121583.1		n.2692-2481G>A		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CACNA1B	ENST00000371372.6	TSL:5 MANE Select	c.228C>T	p.Phe76Phe	synonymous	Exon 1 of 47	ENSP00000360423.1	Q00975-1
	CACNA1B	ENST00000371357.5	TSL:5	c.228C>T	p.Phe76Phe	synonymous	Exon 1 of 46	ENSP00000360408.1	B1AQK7
	CACNA1B	ENST00000371363.5	TSL:5	c.228C>T	p.Phe76Phe	synonymous	Exon 1 of 46	ENSP00000360414.1	B1AQK6

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD2 exomes AF: 0.0000122 AC: 3 AN: 245602 AF XY: 0.0000150

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: 0.0000270

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 1152904 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 555594

African (AFR) AF: 0.00 AC: 0 AN: 24208

American (AMR) AF: 0.00 AC: 0 AN: 13646

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 15414

East Asian (EAS) AF: 0.00 AC: 0 AN: 27938

South Asian (SAS) AF: 0.00 AC: 0 AN: 31314

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 38424

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4660

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 951636

Other (OTH) AF: 0.00 AC: 0 AN: 45664

GnomAD4 genome Cov.: 34

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.26
CADD	Benign	16
DANN	Uncertain	0.98
PhyloP100		5.0
PromoterAI		0.081	Neutral

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: rs139719558; hg19: chr9-140772613;