9-137877990-G-A

Variant names:

• chr9-137877990-G-A
• rs191962352
• NM_000718.4:c.57G>A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000718.4(CACNA1B):​c.57G>A​(p.Glu19Glu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.148 in 1,151,934 control chromosomes in the GnomAD database, including 2,573 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.12 (621 hom., cov: 34)
  • Exomes 𝑓: 0.15 (1952 hom.)
• Consequence: CACNA1B NM_000718.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 2.04

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]

ENSG00000203987 (HGNC:58213):

LOC100133077 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.54).
• BP6: Variant 9-137877990-G-A is Benign according to our data. Variant chr9-137877990-G-A is described in ClinVar as [Benign]. Clinvar id is 1237524.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=2.04 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.159 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1B	NM_000718.4	c.57G>A	p.Glu19Glu	synonymous_variant	Exon 1 of 47	ENST00000371372.6	NP_000709.1
CACNA1B	NM_001243812.2	c.57G>A	p.Glu19Glu	synonymous_variant	Exon 1 of 47		NP_001230741.1
LOC100133077	NR_121583.1	n.2692-2310C>T		intron_variant	Intron 2 of 3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1B	ENST00000371372.6	c.57G>A	p.Glu19Glu	synonymous_variant	Exon 1 of 47	5	NM_000718.4	ENSP00000360423.1
CACNA1B	ENST00000371357.5	c.57G>A	p.Glu19Glu	synonymous_variant	Exon 1 of 46	5		ENSP00000360408.1
CACNA1B	ENST00000371363.5	c.57G>A	p.Glu19Glu	synonymous_variant	Exon 1 of 46	5		ENSP00000360414.1
CACNA1B	ENST00000277551.6	c.57G>A	p.Glu19Glu	synonymous_variant	Exon 1 of 47	5		ENSP00000277551.2

Frequencies

GnomAD3 genomes AF: 0.118 AC: 17562 AN: 148902 Hom.: 623 Cov.: 34

Gnomad AFR AF: 0.0294

Gnomad AMI AF: 0.182

Gnomad AMR AF: 0.162

Gnomad ASJ AF: 0.160

Gnomad EAS AF: 0.00489

Gnomad SAS AF: 0.138

Gnomad FIN AF: 0.154

Gnomad MID AF: 0.100

Gnomad NFE AF: 0.162

Gnomad OTH AF: 0.118

GnomAD3 exomes AF: 0.117 AC: 1322 AN: 11300 Hom.: 0 AF XY: 0.115 AC XY: 644 AN XY: 5594

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.167

Gnomad ASJ exome AF: 0.200

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.100

Gnomad FIN exome AF: 0.115

Gnomad NFE exome AF: 0.124

Gnomad OTH exome AF: 0.130

GnomAD4 exome AF: 0.153 AC: 153455 AN: 1002922 Hom.: 1952 Cov.: 30 AF XY: 0.154 AC XY: 73141 AN XY: 474756

Gnomad4 AFR exome AF: 0.0217

Gnomad4 AMR exome AF: 0.188

Gnomad4 ASJ exome AF: 0.187

Gnomad4 EAS exome AF: 0.00282

Gnomad4 SAS exome AF: 0.140

Gnomad4 FIN exome AF: 0.168

Gnomad4 NFE exome AF: 0.159

Gnomad4 OTH exome AF: 0.144

GnomAD4 genome AF: 0.118 AC: 17551 AN: 149012 Hom.: 621 Cov.: 34 AF XY: 0.119 AC XY: 8622 AN XY: 72698

Gnomad4 AFR AF: 0.0293

Gnomad4 AMR AF: 0.161

Gnomad4 ASJ AF: 0.160

Gnomad4 EAS AF: 0.00491

Gnomad4 SAS AF: 0.138

Gnomad4 FIN AF: 0.154

Gnomad4 NFE AF: 0.162

Gnomad4 OTH AF: 0.117

Alfa AF: 0.0617 Hom.: 0

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jul 28, 2020

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

CACNA1B-related disorder Benign:1

Dec 01, 2023

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.54
CADD	Benign	13
DANN	Uncertain	0.98

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: rs191962352; hg19: chr9-140772442;