chr9-137878081-G-A

Variant names:

• chr9-137878081-G-A
• rs750256540
• NM_000718.4:c.148G>A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_000718.4(CACNA1B):​c.148G>A​(p.Ala50Thr) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CACNA1B NM_000718.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.65

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1B	NM_000718.4	c.148G>A	p.Ala50Thr	missense_variant	Exon 1 of 47	ENST00000371372.6	NP_000709.1
CACNA1B	NM_001243812.2	c.148G>A	p.Ala50Thr	missense_variant	Exon 1 of 47		NP_001230741.1
LOC100133077	NR_121583.1	n.2692-2401C>T		intron_variant	Intron 2 of 3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1B	ENST00000371372.6	c.148G>A	p.Ala50Thr	missense_variant	Exon 1 of 47	5	NM_000718.4	ENSP00000360423.1
CACNA1B	ENST00000371357.5	c.148G>A	p.Ala50Thr	missense_variant	Exon 1 of 46	5		ENSP00000360408.1
CACNA1B	ENST00000371363.5	c.148G>A	p.Ala50Thr	missense_variant	Exon 1 of 46	5		ENSP00000360414.1
CACNA1B	ENST00000277551.6	c.148G>A	p.Ala50Thr	missense_variant	Exon 1 of 47	5		ENSP00000277551.2

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 1190306 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 579170

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 34

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Pathogenic	0.14
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.53	.;.;D;T;.;T
Eigen	Uncertain	0.51
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Pathogenic	1.0	D;D;D;D;D;D
M_CAP	Pathogenic	0.79	D
MetaRNN	Uncertain	0.54	D;D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.4	M;.;M;.;.;.
PrimateAI	Pathogenic	0.94	D
PROVEAN	Uncertain	-3.0	D;.;D;D;D;D
REVEL	Pathogenic	0.68
Sift	Uncertain	0.0010	D;.;D;D;D;D
Sift4G	Benign	0.075	T;T;T;T;T;T
Polyphen		1.0	.;.;.;D;.;.
Vest4		0.46
MutPred		0.32		Gain of glycosylation at A50 (P = 0.0232);Gain of glycosylation at A50 (P = 0.0232);Gain of glycosylation at A50 (P = 0.0232);Gain of glycosylation at A50 (P = 0.0232);Gain of glycosylation at A50 (P = 0.0232);Gain of glycosylation at A50 (P = 0.0232);
MVP		0.94
MPC		0.69
ClinPred		0.99	D
GERP RS		3.5
Varity_R		0.75
gMVP		0.47

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: rs750256540; hg19: chr9-140772533; COSMIC: COSV53111721; COSMIC: COSV53111721;