dbSNP rs12239747: NCSTN:p.Leu212Leu (chr1-160351275-A-G) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. The variant received -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 (★★). Synonymous variant affecting the same amino acid position (i.e. L212L) has been classified as Uncertain significance.

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

Publications

16 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: Genomics England PanelApp, Ambry Genetics, Labcorp Genetics (formerly Invitae)

NCSTN links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 VariationId 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.

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	HGVSp	Effect	Exon Rank	Protein	UniProt
NCSTN	NM_015331.3	MANE Select	c.636A>G	p.Leu212Leu	synonymous	Exon 6 of 17	NP_056146.1	Q92542-1
NCSTN	NM_001290184.2		c.576A>G	p.Leu192Leu	synonymous	Exon 7 of 18	NP_001277113.1	Q92542-2
NCSTN	NM_001349729.2		c.636A>G	p.Leu212Leu	synonymous	Exon 6 of 16	NP_001336658.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
NCSTN	ENST00000294785.10	TSL:1 MANE Select	c.636A>G	p.Leu212Leu	synonymous	Exon 6 of 17	ENSP00000294785.5	Q92542-1
NCSTN	ENST00000368063.6	TSL:1	n.*565A>G		non_coding_transcript_exon	Exon 7 of 18	ENSP00000357042.2	A0A2U3TZL9
NCSTN	ENST00000368063.6	TSL:1	n.*565A>G		3_prime_UTR	Exon 7 of 18	ENSP00000357042.2	A0A2U3TZL9

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

GnomAD2 exomes

AF:

0.0600

AC:

15070

AN:

251300

AF XY:

0.0570

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 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

African (AFR)

AF:

0.232

AC:

7774

AN:

33476

American (AMR)

AF:

0.0557

AC:

2489

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.0388

AC:

1015

AN:

26136

East Asian (EAS)

AF:

0.0364

AC:

1445

AN:

39700

South Asian (SAS)

AF:

0.0471

AC:

4065

AN:

86258

European-Finnish (FIN)

AF:

0.0300

AC:

1600

AN:

53420

Middle Eastern (MID)

AF:

0.0621

AC:

358

AN:

5762

European-Non Finnish (NFE)

AF:

0.0568

AC:

63136

AN:

1111962

Other (OTH)

AF:

0.0628

AC:

3793

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.474

Heterozygous variant carriers

4547

9094

13642

18189

22736

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2484

4968

7452

9936

12420

<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:

0.101

AC:

15294

AN:

152110

Hom.:

1261

Cov.:

AF XY:

0.0972

AC XY:

7228

AN XY:

74354

show subpopulations

African (AFR)

AF:

0.231

AC:

9570

AN:

41472

American (AMR)

AF:

0.0625

AC:

956

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.0400

AC:

139

AN:

3472

East Asian (EAS)

AF:

0.0311

AC:

161

AN:

5174

South Asian (SAS)

AF:

0.0484

AC:

233

AN:

4810

European-Finnish (FIN)

AF:

0.0283

AC:

300

AN:

10590

Middle Eastern (MID)

AF:

0.0748

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0545

AC:

3707

AN:

67992

Other (OTH)

AF:

0.0871

AC:

184

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

643

1287

1930

2574

3217

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

160

320

480

640

800

<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:

0.0731

Hom.:

1161

Bravo

AF:

0.109

Asia WGS

AF:

0.0480

AC:

167

AN:

3478

EpiCase

AF:

0.0575

EpiControl

AF:

0.0580

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.60

CADD

Benign

7.0

(source)

DANN

Benign

0.36

PhyloP100

0.83

PromoterAI

0.0052

Neutral

(source)

Mutation Taster

=99/1

polymorphism (auto)

(source)

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

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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