9-137878012-G-T

Position:

• chr9-137878012-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 1P and 0B. PP2

The NM_000718.4(CACNA1B):​c.79G>T​(p.Gly27Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000133 in 149,938 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 34)
  • Exomes 𝑓: 0.000035 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CACNA1B NM_000718.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:3
• Conservation: PhyloP100: 4.11

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 Uncertain_significance. Variant got 1 ACMG points.

• 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1B	NM_000718.4	c.79G>T	p.Gly27Cys	missense_variant	1/47	ENST00000371372.6	NP_000709.1
CACNA1B	NM_001243812.2	c.79G>T	p.Gly27Cys	missense_variant	1/47		NP_001230741.1
LOC100133077	NR_121583.1	n.2692-2332C>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA1B	ENST00000371372.6	c.79G>T	p.Gly27Cys	missense_variant	1/47	5	NM_000718.4	ENSP00000360423.1
CACNA1B	ENST00000371357.5	c.79G>T	p.Gly27Cys	missense_variant	1/46	5		ENSP00000360408.1
CACNA1B	ENST00000371363.5	c.79G>T	p.Gly27Cys	missense_variant	1/46	5		ENSP00000360414.1
CACNA1B	ENST00000277551.6	c.79G>T	p.Gly27Cys	missense_variant	1/47	5		ENSP00000277551.2

Frequencies

GnomAD3 genomes AF: 0.0000133 AC: 2 AN: 149938 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.0000486

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000352 AC: 38 AN: 1079592 Hom.: 0 Cov.: 32 AF XY: 0.0000445 AC XY: 23 AN XY: 516540

Gnomad4 AFR exome AF: 0.00154

Gnomad4 AMR exome AF: 0.000130

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000110

Gnomad4 OTH exome AF: 0.0000722

GnomAD4 genome AF: 0.0000133 AC: 2 AN: 149938 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 73098

Gnomad4 AFR AF: 0.0000486

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

ExAC AF: 0.0000234 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:2

Uncertain significance, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Neurodevelopmental disorder with seizures and nonepileptic hyperkinetic movements Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

New York Genome Center

Sep 04, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.040
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Benign	0.35	.;.;T;T;.;T
Eigen	Benign	-0.075
Eigen_PC	Benign	-0.12
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Benign	0.62	T;T;T;T;T;T
M_CAP	Pathogenic	0.96	D
MetaRNN	Uncertain	0.70	D;D;D;D;D;D
MetaSVM	Uncertain	0.069	D
MutationAssessor	Pathogenic	3.1	M;.;M;.;.;.
MutationTaster	Benign	1.0	D;N;N;N;N;N
PrimateAI	Pathogenic	0.91	D
PROVEAN	Uncertain	-2.5	N;.;N;N;N;N
REVEL	Uncertain	0.52
Sift	Uncertain	0.018	D;.;D;D;D;D
Sift4G	Uncertain	0.037	D;D;D;D;D;D
Polyphen		0.99	.;.;.;D;.;.
Vest4		0.55
MVP		0.87
MPC		1.7
ClinPred		0.89	D
GERP RS		0.65
Varity_R		0.28
gMVP		0.40

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs758563303; hg19: chr9-140772464;