9-137878195-G-C

Position:

• chr9-137878195-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PP2 PP3_Moderate

The NM_000718.4(CACNA1B):​c.262G>C​(p.Ala88Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 34)
• Consequence: CACNA1B NM_000718.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.47

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]

(HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), CACNA1B. . Gene score misZ 4.5165 (greater than the threshold 3.09). Trascript score misZ 3.231 (greater than threshold 3.09). GenCC has associacion of gene with complex neurodevelopmental disorder with motor features, neurodevelopmental disorder with seizures and nonepileptic hyperkinetic movements, undetermined early-onset epileptic encephalopathy.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.901

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1B	NM_000718.4	c.262G>C	p.Ala88Pro	missense_variant	1/47	ENST00000371372.6	NP_000709.1
LOC100133077	NR_121583.1	n.2692-2515C>G		intron_variant, non_coding_transcript_variant
CACNA1B	NM_001243812.2	c.262G>C	p.Ala88Pro	missense_variant	1/47		NP_001230741.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA1B	ENST00000371372.6	c.262G>C	p.Ala88Pro	missense_variant	1/47	5	NM_000718.4	ENSP00000360423	P4
	ENST00000371390.1	n.2692-2515C>G		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 34

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 13, 2022

The c.262G>C (p.A88P) alteration is located in exon 1 (coding exon 1) of the CACNA1B gene. This alteration results from a G to C substitution at nucleotide position 262, causing the alanine (A) at amino acid position 88 to be replaced by a proline (P). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.35
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.75	.;.;D;T;.;T
Eigen	Uncertain	0.68
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.97	D;D;D;D;D;D
M_CAP	Pathogenic	0.54	D
MetaRNN	Pathogenic	0.90	D;D;D;D;D;D
MetaSVM	Uncertain	0.49	D
MutationAssessor	Pathogenic	3.3	M;.;M;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D
PrimateAI	Pathogenic	0.90	D
PROVEAN	Uncertain	-3.9	D;N;D;D;D;D
REVEL	Pathogenic	0.80
Sift	Uncertain	0.0030	D;T;D;D;D;D
Sift4G	Uncertain	0.0070	D;D;D;D;D;D
Polyphen		1.0	.;.;.;D;.;.
Vest4		0.75
MutPred		0.76		Gain of methylation at K86 (P = 0.0938);Gain of methylation at K86 (P = 0.0938);Gain of methylation at K86 (P = 0.0938);Gain of methylation at K86 (P = 0.0938);Gain of methylation at K86 (P = 0.0938);Gain of methylation at K86 (P = 0.0938);
MVP		0.94
MPC		1.2
ClinPred		0.99	D
GERP RS		3.6
Varity_R		0.98
gMVP		0.89

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr9-140772647;