9-137878161-C-G

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 1P and 16B. PP2 BP4_Strong BP6_Very_Strong BS2

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 -15 ACMG points.

• PP2: Missense variant where missense usually causes diseases, CACNA1B
• 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].
• BS2: High AC in GnomAdExome at 1294 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CACNA1B	NM_000718.4	c.228C>G	p.Phe76Leu	missense_variant	1/47	ENST00000371372.6
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

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CACNA1B	ENST00000371372.6	c.228C>G	p.Phe76Leu	missense_variant	1/47	5	NM_000718.4	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
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;