chr9-137878108-T-C

Position:

• chr9-137878108-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP2

The NM_000718.4(CACNA1B):​c.175T>C​(p.Tyr59His) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CACNA1B NM_000718.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.03

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:):

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), CACNA1B. . Gene score misZ 4.5165 (greater than the threshold 3.09). Trascript score misZ 3.231 (greater than threshold 3.09). GenCC has associacion of gene with complex neurodevelopmental disorder with motor features, neurodevelopmental disorder with seizures and nonepileptic hyperkinetic movements, undetermined early-onset epileptic encephalopathy.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1B	NM_000718.4	c.175T>C	p.Tyr59His	missense_variant	1/47	ENST00000371372.6	NP_000709.1
CACNA1B	NM_001243812.2	c.175T>C	p.Tyr59His	missense_variant	1/47		NP_001230741.1
LOC100133077	NR_121583.1	n.2692-2428A>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA1B	ENST00000371372.6	c.175T>C	p.Tyr59His	missense_variant	1/47	5	NM_000718.4	ENSP00000360423.1
CACNA1B	ENST00000371357.5	c.175T>C	p.Tyr59His	missense_variant	1/46	5		ENSP00000360408.1
CACNA1B	ENST00000371363.5	c.175T>C	p.Tyr59His	missense_variant	1/46	5		ENSP00000360414.1
CACNA1B	ENST00000277551.6	c.175T>C	p.Tyr59His	missense_variant	1/47	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: 1196320 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 582392

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

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing;provider interpretation

Geisinger Autism and Developmental Medicine Institute, Geisinger Health System

Apr 03, 2017

This 18 year old female with moderate intellectual disability, macrocephaly, and seizure disorder was found to carry a missense variant in CACNA1B. More evidence is needed to explore the link between variants in the CACNA1B gene and human disease. While the function of CACNA1B has not been completely defined, mice lacking CACNA1B function had altered memory, learning, sleep-wake cycles, and pain responses as well as aggressive behavior (Kim et al., 2001; Ino et al., 2001). Parental samples are unavailable for this patient, so inheritance is unknown. The variant is not present in population databases. Computational models predict the variant to be probably damaging. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Uncertain	0.13
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.51	.;.;D;T;.;T
Eigen	Uncertain	0.41
Eigen_PC	Uncertain	0.33
FATHMM_MKL	Benign	0.75	D
LIST_S2	Pathogenic	1.0	D;D;D;D;D;D
M_CAP	Pathogenic	0.62	D
MetaRNN	Uncertain	0.59	D;D;D;D;D;D
MetaSVM	Pathogenic	0.95	D
MutationAssessor	Pathogenic	3.4	M;.;M;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D
PrimateAI	Pathogenic	0.94	D
PROVEAN	Uncertain	-3.6	D;.;D;D;D;D
REVEL	Pathogenic	0.80
Sift	Uncertain	0.0010	D;.;D;D;D;D
Sift4G	Uncertain	0.010	D;D;D;D;D;D
Polyphen		0.99	.;.;.;D;.;.
Vest4		0.53
MutPred		0.45		Loss of solvent accessibility (P = 0.0128);Loss of solvent accessibility (P = 0.0128);Loss of solvent accessibility (P = 0.0128);Loss of solvent accessibility (P = 0.0128);Loss of solvent accessibility (P = 0.0128);Loss of solvent accessibility (P = 0.0128);
MVP		0.87
MPC		1.2
ClinPred		0.99	D
GERP RS		3.5
Varity_R		0.81
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: rs1564867162; hg19: chr9-140772560;