Variant chr9-130219765-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_014286.4(NCS1):c.269C>T(p.Ser90Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000342 in 1,461,888 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000034 ( 0 hom. )

Consequence

NCS1
NM_014286.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.84

Variant links:

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]

NCS1 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.94

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NCS1	NM_014286.4 linkuse as main transcript	c.269C>T	p.Ser90Leu	missense_variant	4/8	ENST00000372398.6	NP_055101.2
NCS1	NM_001128826.2 linkuse as main transcript	c.215C>T	p.Ser72Leu	missense_variant	4/8		NP_001122298.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NCS1	ENST00000372398.6 linkuse as main transcript	c.269C>T	p.Ser90Leu	missense_variant	4/8	1	NM_014286.4	ENSP00000361475	P1	P62166-1
NCS1	ENST00000630865.1 linkuse as main transcript	c.215C>T	p.Ser72Leu	missense_variant	4/8	3		ENSP00000486695		P62166-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000342

AC:

AN:

1461888

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727248

show subpopulations

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:

0.0000187

Gnomad4 NFE exome

AF:

0.00000360

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 26, 2022

The c.269C>T (p.S90L) 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 269, causing the serine (S) at amino acid position 90 to be replaced by a leucine (L). 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

0.29

BayesDel_noAF

Pathogenic

0.18

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.64

D;.

Eigen

Pathogenic

0.74

Eigen_PC

Uncertain

0.57

FATHMM_MKL

Uncertain

0.94

LIST_S2

Pathogenic

0.99

D;D

M_CAP

Uncertain

0.13

MetaRNN

Pathogenic

0.94

D;D

MetaSVM

Uncertain

0.13

MutationAssessor

Pathogenic

3.2

M;.

MutationTaster

Benign

1.0

D;D

PrimateAI

Pathogenic

0.88

PROVEAN

Pathogenic

-5.5

D;.

REVEL

Uncertain

0.58

Sift

Pathogenic

0.0

D;.

Sift4G

Pathogenic

0.0010

D;D

Polyphen

1.0

D;.

Vest4

0.89

MutPred

0.81

Loss of catalytic residue at S90 (P = 0.0211);.;

MVP

0.81

MPC

2.4

ClinPred

1.0

GERP RS

4.6

Varity_R

0.89

gMVP

0.95

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

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over