9-137882854-C-G

Position:

• chr9-137882854-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:3
• 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]

ENSG00000203987 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -9 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.
• 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	Protein	UniProt
CACNA1B	NM_000718.4	c.501C>G	p.Asn167Lys	missense_variant	3/47	ENST00000371372.6	NP_000709.1
CACNA1B	NM_001243812.2	c.501C>G	p.Asn167Lys	missense_variant	3/47		NP_001230741.1
LOC100133077	NR_121583.1	n.2674G>C		non_coding_transcript_exon_variant	2/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA1B	ENST00000371372.6	c.501C>G	p.Asn167Lys	missense_variant	3/47	5	NM_000718.4	ENSP00000360423.1
CACNA1B	ENST00000371357.5	c.501C>G	p.Asn167Lys	missense_variant	3/46	5		ENSP00000360408.1
CACNA1B	ENST00000371363.5	c.501C>G	p.Asn167Lys	missense_variant	3/46	5		ENSP00000360414.1
CACNA1B	ENST00000277551.6	c.501C>G	p.Asn167Lys	missense_variant	3/47	5		ENSP00000277551.2

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:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 30, 2021	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Neurodevelopmental disorder with seizures and nonepileptic hyperkinetic movements Benign:1

Benign, criteria provided, single submitter

clinical testing

Mendelics

May 28, 2019

- -

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
DEOGEN2	Pathogenic	0.96	.;.;D;D;.;D
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;.;.;.
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;