1-160354113-C-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_015331.3(NCSTN):c.1180-5C>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0515 in 1,613,694 control chromosomes in the GnomAD database, including 2,388 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.055 ( 250 hom., cov: 32)

Exomes 𝑓: 0.051 ( 2138 hom. )

Consequence

NCSTN
NM_015331.3 splice_region, intron

Scores

Splicing: ADA: 0.001802

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -0.0220

Publications

12 publications found

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 Gene-Disease associations (from GenCC):

acne inversa, familial, 1
Inheritance: AD Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Genomics England PanelApp

NCSTN links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.82).

BP6

Variant 1-160354113-C-G is Benign according to our data. Variant chr1-160354113-C-G is described in ClinVar as Benign. ClinVar VariationId is 1165589.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0789 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015331.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
NCSTN	NM_015331.3	MANE Select	c.1180-5C>G	splice_region intron	N/A	NP_056146.1	Q92542-1
NCSTN	NM_001290184.2		c.1120-5C>G	splice_region intron	N/A	NP_001277113.1	Q92542-2
NCSTN	NM_001349729.2		c.1180-5C>G	splice_region intron	N/A	NP_001336658.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
NCSTN	ENST00000294785.10	TSL:1 MANE Select	c.1180-5C>G	splice_region intron	N/A	ENSP00000294785.5	Q92542-1
NCSTN	ENST00000368063.6	TSL:1	n.*1109-5C>G	splice_region intron	N/A	ENSP00000357042.2	A0A2U3TZL9
NCSTN	ENST00000913597.1		c.1234-5C>G	splice_region intron	N/A	ENSP00000583656.1

Frequencies

GnomAD3 genomes

AF:

0.0552

AC:

8389

AN:

152066

Hom.:

248

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0811

Gnomad AMI

AF:

0.0242

Gnomad AMR

AF:

0.0417

Gnomad ASJ

AF:

0.0401

Gnomad EAS

AF:

0.000579

Gnomad SAS

AF:

0.0367

Gnomad FIN

AF:

0.0277

Gnomad MID

AF:

0.0633

Gnomad NFE

AF:

0.0532

Gnomad OTH

AF:

0.0593

GnomAD2 exomes

AF:

0.0418

AC:

10494

AN:

251184

AF XY:

0.0422

show subpopulations

Gnomad AFR exome

AF:

0.0798

Gnomad AMR exome

AF:

0.0250

Gnomad ASJ exome

AF:

0.0396

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0266

Gnomad NFE exome

AF:

0.0524

Gnomad OTH exome

AF:

0.0428

GnomAD4 exome

AF:

0.0512

AC:

74764

AN:

1461510

Hom.:

2138

Cov.:

AF XY:

0.0506

AC XY:

36792

AN XY:

727084

show subpopulations

African (AFR)

AF:

0.0800

AC:

2678

AN:

33458

American (AMR)

AF:

0.0281

AC:

1255

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.0381

AC:

995

AN:

26132

East Asian (EAS)

AF:

0.000101

AC:

AN:

39700

South Asian (SAS)

AF:

0.0379

AC:

3271

AN:

86254

European-Finnish (FIN)

AF:

0.0292

AC:

1562

AN:

53416

Middle Eastern (MID)

AF:

0.0491

AC:

283

AN:

5766

European-Non Finnish (NFE)

AF:

0.0556

AC:

61766

AN:

1111682

Other (OTH)

AF:

0.0489

AC:

2950

AN:

60384

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

Heterozygous variant carriers

3672

7343

11015

14686

18358

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2314

4628

6942

9256

11570

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0552

AC:

8404

AN:

152184

Hom.:

250

Cov.:

AF XY:

0.0531

AC XY:

3949

AN XY:

74410

show subpopulations

African (AFR)

AF:

0.0811

AC:

3367

AN:

41492

American (AMR)

AF:

0.0416

AC:

637

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.0401

AC:

139

AN:

3468

East Asian (EAS)

AF:

0.000580

AC:

AN:

5172

South Asian (SAS)

AF:

0.0374

AC:

180

AN:

4816

European-Finnish (FIN)

AF:

0.0277

AC:

294

AN:

10614

Middle Eastern (MID)

AF:

0.0680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0532

AC:

3618

AN:

68008

Other (OTH)

AF:

0.0587

AC:

124

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

393

787

1180

1574

1967

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

192

288

384

480

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0422

Hom.:

Bravo

AF:

0.0573

Asia WGS

AF:

0.0210

AC:

AN:

3478

EpiCase

AF:

0.0555

EpiControl

AF:

0.0553

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.82

CADD

Benign

9.5

(source)

DANN

Benign

0.46

PhyloP100

-0.022

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.0018

dbscSNV1_RF

Benign

0.040

SpliceAI score (max)

0.41

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.41

Position offset: -29

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over