dbSNP rs4422842: CACNA1B:p.Asn167Lys (chr9-137882854-C-A) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_000718.4(CACNA1B):c.501C>A(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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Benign in ClinVar.

Frequency

Genomes: not found (cov: 32)

Consequence

CACNA1B
NM_000718.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.13

Publications

36 publications found

Variant links:

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: Illumina, Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
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 links:

ENSG00000203987 (HGNC:58213):

ENSG00000203987 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.006344497).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
CACNA1B	NM_000718.4 link	c.501C>A	p.Asn167Lys	missense_variant	Exon 3 of 47	ENST00000371372.6	NP_000709.1
CACNA1B	NM_001243812.2 link	c.501C>A	p.Asn167Lys	missense_variant	Exon 3 of 47		NP_001230741.1
CACNA1B-AS2	NR_121583.1 link	n.2674G>T		non_coding_transcript_exon_variant	Exon 2 of 4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
CACNA1B	ENST00000371372.6 link	c.501C>A	p.Asn167Lys	missense_variant	Exon 3 of 47	5	NM_000718.4	ENSP00000360423.1
CACNA1B	ENST00000371357.5 link	c.501C>A	p.Asn167Lys	missense_variant	Exon 3 of 46	5		ENSP00000360408.1
CACNA1B	ENST00000371363.5 link	c.501C>A	p.Asn167Lys	missense_variant	Exon 3 of 46	5		ENSP00000360414.1
CACNA1B	ENST00000277551.6 link	c.501C>A	p.Asn167Lys	missense_variant	Exon 3 of 47	5		ENSP00000277551.2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.0000481

AC:

AN:

249262

AF XY:

0.0000444

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000669

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000363

Hom.:

ExAC

AF:

0.000140

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.20

BayesDel_noAF

Uncertain

0.040

CADD

Benign

4.7

(source)

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

LIST_S2

Benign

0.81

T;T;T;T;T;T

MetaRNN

Benign

0.0063

T;T;T;T;T;T

MetaSVM

Pathogenic

1.0

MutationAssessor

Pathogenic

5.0

H;.;H;.;.;.

PhyloP100

-1.1

PrimateAI

Uncertain

0.77

PROVEAN

Pathogenic

-5.4

D;.;D;D;D;D

REVEL

Pathogenic

0.73

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);

MVP

0.95

MPC

1.0

ClinPred

0.73

GERP RS

-4.7

Varity_R

0.93

gMVP

1.0

Mutation Taster

=86/14

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over