chr9-138102721-A-G

Variant names:

• chr9-138102721-A-G
• rs1554758384
• NM_000718.4:c.5233A>G

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_000718.4(CACNA1B):​c.5233A>G​(p.Ser1745Gly) variant causes a missense change. The variant allele was found at a frequency of 0.000000686 in 1,458,490 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: CACNA1B NM_000718.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.64
• Publications: 0 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

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.34095773).

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.5233A>G	p.Ser1745Gly	missense	Exon 38 of 47	NP_000709.1	Q00975-1
	CACNA1B	NM_001243812.2		c.5233A>G	p.Ser1745Gly	missense	Exon 38 of 47	NP_001230741.1	Q00975-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CACNA1B	ENST00000371372.6	TSL:5 MANE Select	c.5233A>G	p.Ser1745Gly	missense	Exon 38 of 47	ENSP00000360423.1	Q00975-1
	CACNA1B	ENST00000371357.5	TSL:5	c.5230A>G	p.Ser1744Gly	missense	Exon 37 of 46	ENSP00000360408.1	B1AQK7
	CACNA1B	ENST00000371363.5	TSL:5	c.5227A>G	p.Ser1743Gly	missense	Exon 37 of 46	ENSP00000360414.1	B1AQK6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.86e-7 AC: 1 AN: 1458490 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 725608

African (AFR) AF: 0.00 AC: 0 AN: 33426

American (AMR) AF: 0.00 AC: 0 AN: 44556

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26038

East Asian (EAS) AF: 0.00 AC: 0 AN: 39582

South Asian (SAS) AF: 0.00 AC: 0 AN: 85950

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53258

Middle Eastern (MID) AF: 0.000174 AC: 1 AN: 5758

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1109698

Other (OTH) AF: 0.00 AC: 0 AN: 60224

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Dystonia 23 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.089
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.040
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.83	D
Eigen	Benign	-0.13
Eigen_PC	Benign	0.053
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.80	T
M_CAP	Benign	0.047	D
MetaRNN	Benign	0.34	T
MetaSVM	Uncertain	0.56	D
MutationAssessor	Benign	1.3	L
PhyloP100		3.6
PrimateAI	Uncertain	0.58	T
PROVEAN	Uncertain	-2.4	N
REVEL	Uncertain	0.34
Sift	Benign	0.037	D
Sift4G	Benign	0.15	T
Polyphen		0.092	B
Vest4		0.45
MutPred		0.41		Loss of catalytic residue at S1744 (P = 0.0696)
MVP		0.88
MPC		1.3
ClinPred		0.62	D
GERP RS		4.7
Varity_R		0.16
gMVP		0.79
Mutation Taster		=80/20	polymorphism

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: rs1554758384; hg19: chr9-140997173; COSMIC: COSV53121841;