1-160354113-C-G

Variant names:

• chr1-160354113-C-G
• rs7528638
• NM_015331.3:c.1180-5C>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

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

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

ACMG classification

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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NCSTN	NM_015331.3	c.1180-5C>G		splice_region_variant, intron_variant	Intron 10 of 16	ENST00000294785.10	NP_056146.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NCSTN	ENST00000294785.10	c.1180-5C>G		splice_region_variant, intron_variant	Intron 10 of 16	1	NM_015331.3	ENSP00000294785.5

Frequencies

GnomAD3 genomes AF: 0.0552 AC: 8389 AN: 152066 Hom.: 248 Cov.: 32

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

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.: 31 AF XY: 0.0506 AC XY: 36792 AN XY: 727084

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: 4 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

GnomAD4 genome AF: 0.0552 AC: 8404 AN: 152184 Hom.: 250 Cov.: 32 AF XY: 0.0531 AC XY: 3949 AN XY: 74410

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: 3 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: 20 AN: 294

European-Non Finnish (NFE) AF: 0.0532 AC: 3618 AN: 68008

Other (OTH) AF: 0.0587 AC: 124 AN: 2114

Alfa AF: 0.0422 Hom.: 44

Bravo AF: 0.0573

Asia WGS AF: 0.0210 AC: 74 AN: 3478

EpiCase AF: 0.0555

EpiControl AF: 0.0553

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

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

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	9.5
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)

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

Other links and lift over

dbSNP: rs7528638; hg19: chr1-160323903;