9-130226430-T-G

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 0P and 11B. BP4_Moderate BP7 BA1

The NM_014286.4(NCS1):c.516T>G(p.Gly172=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.326 in 1,612,954 control chromosomes in the GnomAD database, including 89,139 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.36 (10122 hom., cov: 32)
  • Exomes 𝑓: 0.32 (79017 hom.)
• Consequence: NCS1 NM_014286.4 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.37

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 Benign. Variant got -11 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.45).
• BP7: Synonymous conserved (PhyloP=-1.37 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.44 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NCS1	NM_014286.4	c.516T>G	p.Gly172=	synonymous_variant	7/8	ENST00000372398.6
NCS1	NM_001128826.2	c.462T>G	p.Gly154=	synonymous_variant	7/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NCS1	ENST00000372398.6	c.516T>G	p.Gly172=	synonymous_variant	7/8	1	NM_014286.4	P1
NCS1	ENST00000630865.1	c.462T>G	p.Gly154=	synonymous_variant	7/8	3

Frequencies

GnomAD3 genomes AF: 0.356 AC: 53977 AN: 151732 Hom.: 10095 Cov.: 32

Gnomad AFR AF: 0.445

Gnomad AMI AF: 0.246

Gnomad AMR AF: 0.416

Gnomad ASJ AF: 0.361

Gnomad EAS AF: 0.168

Gnomad SAS AF: 0.197

Gnomad FIN AF: 0.228

Gnomad MID AF: 0.285

Gnomad NFE AF: 0.334

Gnomad OTH AF: 0.374

GnomAD3 exomes AF: 0.329 AC: 82493 AN: 250692 Hom.: 15060 AF XY: 0.314 AC XY: 42557 AN XY: 135498

Gnomad AFR exome AF: 0.444

Gnomad AMR exome AF: 0.524

Gnomad ASJ exome AF: 0.359

Gnomad EAS exome AF: 0.167

Gnomad SAS exome AF: 0.192

Gnomad FIN exome AF: 0.240

Gnomad NFE exome AF: 0.330

Gnomad OTH exome AF: 0.336

GnomAD4 exome AF: 0.323 AC: 471662 AN: 1461104 Hom.: 79017 Cov.: 37 AF XY: 0.318 AC XY: 231377 AN XY: 726846

Gnomad4 AFR exome AF: 0.447

Gnomad4 AMR exome AF: 0.512

Gnomad4 ASJ exome AF: 0.352

Gnomad4 EAS exome AF: 0.184

Gnomad4 SAS exome AF: 0.198

Gnomad4 FIN exome AF: 0.249

Gnomad4 NFE exome AF: 0.329

Gnomad4 OTH exome AF: 0.322

GnomAD4 genome AF: 0.356 AC: 54048 AN: 151850 Hom.: 10122 Cov.: 32 AF XY: 0.347 AC XY: 25762 AN XY: 74186

Gnomad4 AFR AF: 0.445

Gnomad4 AMR AF: 0.417

Gnomad4 ASJ AF: 0.361

Gnomad4 EAS AF: 0.168

Gnomad4 SAS AF: 0.198

Gnomad4 FIN AF: 0.228

Gnomad4 NFE AF: 0.334

Gnomad4 OTH AF: 0.371

Alfa AF: 0.333 Hom.: 17915

Bravo AF: 0.377

Asia WGS AF: 0.230 AC: 798 AN: 3478

EpiCase AF: 0.325

EpiControl AF: 0.331

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.45
Cadd	Benign	2.8
Dann	Benign	0.69
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs2277200; hg19: chr9-132988709; COSMIC: COSV64962259;