9-137882854-C-G

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 3P and 12B. PM2 PP2 BP4_Strong BP6_Very_Strong

The NM_000718.4(CACNA1B):c.501C>G(p.Asn167Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CACNA1B NM_000718.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.13

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 Benign. Variant got -9 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, CACNA1B
• BP4: Computational evidence support a benign effect (MetaRNN=0.0038129091).
• BP6: Variant 9-137882854-C-G is Benign according to our data. Variant chr9-137882854-C-G is described in ClinVar as [Benign]. Clinvar id is 802555.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-137882854-C-G is described in Lovd as [Benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CACNA1B	NM_000718.4	c.501C>G	p.Asn167Lys	missense_variant	3/47	ENST00000371372.6
LOC100133077	NR_121583.1	n.2674G>C		non_coding_transcript_exon_variant	2/4
CACNA1B	NM_001243812.2	c.501C>G	p.Asn167Lys	missense_variant	3/47

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CACNA1B	ENST00000371372.6	c.501C>G	p.Asn167Lys	missense_variant	3/47	5	NM_000718.4	P4
	ENST00000371390.1	n.2674G>C		non_coding_transcript_exon_variant	2/4	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.245 Hom.: 0

ExAC AF: 0.499 AC: 60416

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Neurodevelopmental disorder with seizures and nonepileptic hyperkinetic movements Benign:1

Benign, criteria provided, single submitter

clinical testing

Mendelics

May 28, 2019

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 30, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.040
Cadd	Benign	5.3
Dann	Benign	0.90
Eigen	Benign	-0.61
Eigen_PC	Benign	-0.93
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.81	T;T;T;T;T;T
MetaRNN	Benign	0.0038	T;T;T;T;T;T
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	5.0	H;.;H;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D
PrimateAI	Uncertain	0.77	T
PROVEAN	Pathogenic	-5.4	D;.;D;D;D;D
REVEL	Pathogenic	0.75
Sift	Uncertain	0.010	D;.;D;D;D;D
Sift4G	Pathogenic	0.0010	D;D;D;D;D;D
Polyphen		1.0	.;.;.;D;.;.
Vest4		0.53
MutPred		0.52		Gain of methylation at N167 (P = 0.0022);Gain of methylation at N167 (P = 0.0022);Gain of methylation at N167 (P = 0.0022);Gain of methylation at N167 (P = 0.0022);Gain of methylation at N167 (P = 0.0022);Gain of methylation at N167 (P = 0.0022);
MPC		1.0
ClinPred		0.15	T
GERP RS		-4.7
Varity_R		0.93
gMVP		1.0

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs4422842; hg19: chr9-140777306; COSMIC: COSV53112319;