9-137878161-C-G

Position:

• chr9-137878161-C-G

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 1P and 12B. PP2 BP4_Strong BP6_Very_Strong

The NM_000718.4(CACNA1B):​c.228C>G​(p.Phe76Leu) variant causes a missense change. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0 (0 hom., cov: 34)
  • Exomes 𝑓: 0.000029 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CACNA1B NM_000718.4 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 5.04

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 -11 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.00974983).
• BP6: Variant 9-137878161-C-G is Benign according to our data. Variant chr9-137878161-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 1317106.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-137878161-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.228C>G	p.Phe76Leu	missense_variant	1/47	ENST00000371372.6	NP_000709.1
LOC100133077	NR_121583.1	n.2692-2481G>C		intron_variant, non_coding_transcript_variant
CACNA1B	NM_001243812.2	c.228C>G	p.Phe76Leu	missense_variant	1/47		NP_001230741.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA1B	ENST00000371372.6	c.228C>G	p.Phe76Leu	missense_variant	1/47	5	NM_000718.4	ENSP00000360423	P4
	ENST00000371390.1	n.2692-2481G>C		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.00 AC: 0 AN: 151552 Hom.: 0 Cov.: 34 FAILED QC

Gnomad AFR AF: 0.00

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

GnomAD3 exomes AF: 0.00527 AC: 1294 AN: 245602 Hom.: 2 AF XY: 0.00607 AC XY: 811 AN XY: 133610

Gnomad AFR exome AF: 0.000133

Gnomad AMR exome AF: 0.00367

Gnomad ASJ exome AF: 0.0200

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0138

Gnomad FIN exome AF: 0.000700

Gnomad NFE exome AF: 0.00445

Gnomad OTH exome AF: 0.00739

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000286 AC: 33 AN: 1151980 Hom.: 0 Cov.: 33 AF XY: 0.0000306 AC XY: 17 AN XY: 555168

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000147

Gnomad4 ASJ exome AF: 0.000260

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000256

Gnomad4 FIN exome AF: 0.0000260

Gnomad4 NFE exome AF: 0.0000158

Gnomad4 OTH exome AF: 0.0000438

GnomAD4 genome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 151552 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 74024

Gnomad4 AFR AF: 0.00

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

Alfa AF: 0.00629 Hom.: 0

ESP6500AA AF: 0.000241 AC: 1

ESP6500EA AF: 0.00464 AC: 39

ExAC AF: 0.00551 AC: 667

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 23, 2022	See Variant Classification Assertion Criteria. -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	CACNA1B: BS1 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Uncertain	0.050	T
BayesDel_noAF	Benign	-0.17
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.66	.;.;D;T;.;T
Eigen	Benign	0.13
Eigen_PC	Benign	0.15
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Pathogenic	0.98	D;D;D;D;D;D
MetaRNN	Benign	0.0097	T;T;T;T;T;T
MetaSVM	Benign	-0.68	T
MutationAssessor	Uncertain	2.6	M;.;M;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D
PrimateAI	Pathogenic	0.95	D
PROVEAN	Pathogenic	-4.4	D;.;D;D;D;D
REVEL	Uncertain	0.34
Sift	Benign	0.13	T;.;D;D;D;D
Sift4G	Benign	0.15	T;T;T;T;T;T
Polyphen		0.70	.;.;.;P;.;.
Vest4		0.62
MutPred		0.74		Loss of sheet (P = 0.1158);Loss of sheet (P = 0.1158);Loss of sheet (P = 0.1158);Loss of sheet (P = 0.1158);Loss of sheet (P = 0.1158);Loss of sheet (P = 0.1158);
MVP		0.64
MPC		0.78
ClinPred		0.069	T
GERP RS		3.5
Varity_R		0.86
gMVP		0.77

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: rs139719558; hg19: chr9-140772613; COSMIC: COSV99055308; COSMIC: COSV99055308;