rs12239747

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_015331.3(NCSTN):c.636A>G(p.Leu212Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0626 in 1,613,942 control chromosomes in the GnomAD database, including 4,435 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.10 ( 1261 hom., cov: 32)

Exomes 𝑓: 0.059 ( 3174 hom. )

Consequence

NCSTN
NM_015331.3 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 0.827

Variant links:

Genes affected

NCSTN (HGNC:17091): (nicastrin) This gene encodes a type I transmembrane glycoprotein that is an integral component of the multimeric gamma-secretase complex. The encoded protein cleaves integral membrane proteins, including Notch receptors and beta-amyloid precursor protein, and may be a stabilizing cofactor required for gamma-secretase complex assembly. The cleavage of beta-amyloid precursor protein yields amyloid beta peptide, the main component of the neuritic plaque and the hallmark lesion in the brains of patients with Alzheimer's disease; however, the nature of the encoded protein's role in Alzheimer's disease is not known for certain. Mutations in this gene are associated with familial acne inversa. A pseudogene of this gene is present on chromosome 21. Alternatively spliced transcript variants of this gene have been described, but the full-length nature of some of these variants has not been determined. [provided by RefSeq, Feb 2014]

NCSTN links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.6).

BP6

Variant 1-160351275-A-G is Benign according to our data. Variant chr1-160351275-A-G is described in ClinVar as [Benign]. Clinvar id is 403222.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.827 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.227 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NCSTN	NM_015331.3 link	c.636A>G	p.Leu212Leu	synonymous_variant	Exon 6 of 17	ENST00000294785.10	NP_056146.1	Q92542-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NCSTN	ENST00000294785.10 link	c.636A>G	p.Leu212Leu	synonymous_variant	Exon 6 of 17	1	NM_015331.3	ENSP00000294785.5		Q92542-1

Frequencies

GnomAD3 genomes

AF:

0.100

AC:

15265

AN:

151992

Hom.:

1260

Cov.:

show subpopulations

Gnomad AFR

AF:

0.231

Gnomad AMI

AF:

0.0242

Gnomad AMR

AF:

0.0626

Gnomad ASJ

AF:

0.0400

Gnomad EAS

AF:

0.0314

Gnomad SAS

AF:

0.0482

Gnomad FIN

AF:

0.0283

Gnomad MID

AF:

0.0728

Gnomad NFE

AF:

0.0545

Gnomad OTH

AF:

0.0866

GnomAD3 exomes

AF:

0.0600

AC:

15070

AN:

251300

Hom.:

732

AF XY:

0.0570

AC XY:

7746

AN XY:

135822

show subpopulations

Gnomad AFR exome

AF:

0.234

Gnomad AMR exome

AF:

0.0545

Gnomad ASJ exome

AF:

0.0401

Gnomad EAS exome

AF:

0.0247

Gnomad SAS exome

AF:

0.0478

Gnomad FIN exome

AF:

0.0272

Gnomad NFE exome

AF:

0.0540

Gnomad OTH exome

AF:

0.0551

GnomAD4 exome

AF:

0.0586

AC:

85675

AN:

1461832

Hom.:

3174

Cov.:

AF XY:

0.0575

AC XY:

41798

AN XY:

727226

show subpopulations

Gnomad4 AFR exome

AF:

0.232

Gnomad4 AMR exome

AF:

0.0557

Gnomad4 ASJ exome

AF:

0.0388

Gnomad4 EAS exome

AF:

0.0364

Gnomad4 SAS exome

AF:

0.0471

Gnomad4 FIN exome

AF:

0.0300

Gnomad4 NFE exome

AF:

0.0568

Gnomad4 OTH exome

AF:

0.0628

GnomAD4 genome

AF:

0.101

AC:

15294

AN:

152110

Hom.:

1261

Cov.:

AF XY:

0.0972

AC XY:

7228

AN XY:

74354

show subpopulations

Gnomad4 AFR

AF:

0.231

Gnomad4 AMR

AF:

0.0625

Gnomad4 ASJ

AF:

0.0400

Gnomad4 EAS

AF:

0.0311

Gnomad4 SAS

AF:

0.0484

Gnomad4 FIN

AF:

0.0283

Gnomad4 NFE

AF:

0.0545

Gnomad4 OTH

AF:

0.0871

Alfa

AF:

0.0684

Hom.:

723

Bravo

AF:

0.109

Asia WGS

AF:

0.0480

AC:

167

AN:

3478

EpiCase

AF:

0.0575

EpiControl

AF:

0.0580

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified

Benign:1

Mar 29, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.60

CADD

Benign

7.0

DANN

Benign

0.36

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over