chr9-130219776-C-T

Position:

• chr9-130219776-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_014286.4(NCS1):​c.280C>T​(p.Arg94Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,884 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: NCS1 NM_014286.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.296

Genes affected

NCS1 (HGNC:3953): (neuronal calcium sensor 1) This gene is a member of the neuronal calcium sensor gene family, which encode calcium-binding proteins expressed predominantly in neurons. The protein encoded by this gene regulates G protein-coupled receptor phosphorylation in a calcium-dependent manner and can substitute for calmodulin. The protein is associated with secretory granules and modulates synaptic transmission and synaptic plasticity. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.833

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NCS1	NM_014286.4	c.280C>T	p.Arg94Trp	missense_variant	4/8	ENST00000372398.6	NP_055101.2
NCS1	NM_001128826.2	c.226C>T	p.Arg76Trp	missense_variant	4/8		NP_001122298.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NCS1	ENST00000372398.6	c.280C>T	p.Arg94Trp	missense_variant	4/8	1	NM_014286.4	ENSP00000361475.3
NCS1	ENST00000630865.1	c.226C>T	p.Arg76Trp	missense_variant	4/8	3		ENSP00000486695.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461884 Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2 AN XY: 727246

Gnomad4 AFR exome AF: 0.0000299

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: 0.00000180

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 02, 2024

The c.280C>T (p.R94W) alteration is located in exon 4 (coding exon 4) of the NCS1 gene. This alteration results from a C to T substitution at nucleotide position 280, causing the arginine (R) at amino acid position 94 to be replaced by a tryptophan (W). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.040
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.52	D;.
Eigen	Benign	-0.095
Eigen_PC	Benign	-0.42
FATHMM_MKL	Benign	0.25	N
LIST_S2	Pathogenic	1.0	D;D
M_CAP	Uncertain	0.14	D
MetaRNN	Pathogenic	0.83	D;D
MetaSVM	Uncertain	0.023	D
MutationAssessor	Pathogenic	4.0	H;.
PrimateAI	Pathogenic	0.93	D
PROVEAN	Pathogenic	-7.3	D;.
REVEL	Uncertain	0.44
Sift	Pathogenic	0.0	D;.
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;.
Vest4		0.83
MutPred		0.60		Loss of disorder (P = 0.0222);.;
MVP		0.72
MPC		2.6
ClinPred		0.99	D
GERP RS		-3.0
Varity_R		0.91
gMVP		0.89

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: rs1833249186; hg19: chr9-132982055; COSMIC: COSV64962704; COSMIC: COSV64962704;