rs191962352

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chr9-137877990-G-A
• chr9-137877990-G-C

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 1 publications found

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: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P, Illumina
• 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-AS2 (HGNC:58213):

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000718.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CACNA1B	NM_000718.4	MANE Select	c.57G>A	p.Glu19Glu	synonymous	Exon 1 of 47	NP_000709.1	Q00975-1
	CACNA1B	NM_001243812.2		c.57G>A	p.Glu19Glu	synonymous	Exon 1 of 47	NP_001230741.1	Q00975-2
	CACNA1B-AS2	NR_121583.1		n.2692-2310C>T		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CACNA1B	ENST00000371372.6	TSL:5 MANE Select	c.57G>A	p.Glu19Glu	synonymous	Exon 1 of 47	ENSP00000360423.1	Q00975-1
	CACNA1B	ENST00000371357.5	TSL:5	c.57G>A	p.Glu19Glu	synonymous	Exon 1 of 46	ENSP00000360408.1	B1AQK7
	CACNA1B	ENST00000371363.5	TSL:5	c.57G>A	p.Glu19Glu	synonymous	Exon 1 of 46	ENSP00000360414.1	B1AQK6

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

GnomAD2 exomes AF: 0.117 AC: 1322 AN: 11300 AF XY: 0.115

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 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

African (AFR) AF: 0.0217 AC: 433 AN: 19976

American (AMR) AF: 0.188 AC: 1114 AN: 5920

Ashkenazi Jewish (ASJ) AF: 0.187 AC: 2013 AN: 10764

East Asian (EAS) AF: 0.00282 AC: 50 AN: 17744

South Asian (SAS) AF: 0.140 AC: 2613 AN: 18690

European-Finnish (FIN) AF: 0.168 AC: 4418 AN: 26322

Middle Eastern (MID) AF: 0.125 AC: 347 AN: 2776

European-Non Finnish (NFE) AF: 0.159 AC: 137022 AN: 862970

Other (OTH) AF: 0.144 AC: 5445 AN: 37760

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

African (AFR) AF: 0.0293 AC: 1208 AN: 41232

American (AMR) AF: 0.161 AC: 2418 AN: 14996

Ashkenazi Jewish (ASJ) AF: 0.160 AC: 548 AN: 3420

East Asian (EAS) AF: 0.00491 AC: 25 AN: 5096

South Asian (SAS) AF: 0.138 AC: 663 AN: 4794

European-Finnish (FIN) AF: 0.154 AC: 1479 AN: 9580

Middle Eastern (MID) AF: 0.100 AC: 29 AN: 290

European-Non Finnish (NFE) AF: 0.162 AC: 10775 AN: 66636

Other (OTH) AF: 0.117 AC: 242 AN: 2066

Alfa AF: 0.0617 Hom.: 0

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	CACNA1B-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.54
CADD	Benign	13
DANN	Uncertain	0.98
PhyloP100		2.0
PromoterAI		-0.0037	Neutral
Mutation Taster		=298/2	polymorphism (auto)

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

Other links and lift over

dbSNP: rs191962352; hg19: chr9-140772442; COSMIC: COSV108068202; COSMIC: COSV108068202;