chr1-160347231-C-T

Variant names:

• chr1-160347231-C-T
• rs6668576
• NM_015331.3:c.191-1768C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_015331.3(NCSTN):​c.191-1768C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.432 in 152,028 control chromosomes in the GnomAD database, including 15,147 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 0.43 (15147 hom., cov: 32)
• Consequence: NCSTN NM_015331.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0920
• Publications: 14 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.593 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NCSTN	NM_015331.3	MANE Select	c.191-1768C>T		intron	N/A	NP_056146.1
	NCSTN	NM_001290184.2		c.131-1768C>T		intron	N/A	NP_001277113.1
	NCSTN	NM_001349729.2		c.191-1768C>T		intron	N/A	NP_001336658.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NCSTN	ENST00000294785.10	TSL:1 MANE Select	c.191-1768C>T		intron	N/A	ENSP00000294785.5
	NCSTN	ENST00000368063.6	TSL:1	n.*120-1768C>T		intron	N/A	ENSP00000357042.2
	NCSTN	ENST00000699555.1		n.512C>T		non_coding_transcript_exon	Exon 1 of 3

Frequencies

GnomAD3 genomes AF: 0.432 AC: 65601 AN: 151908 Hom.: 15150 Cov.: 32

Gnomad AFR AF: 0.258

Gnomad AMI AF: 0.536

Gnomad AMR AF: 0.475

Gnomad ASJ AF: 0.440

Gnomad EAS AF: 0.343

Gnomad SAS AF: 0.612

Gnomad FIN AF: 0.501

Gnomad MID AF: 0.547

Gnomad NFE AF: 0.508

Gnomad OTH AF: 0.466

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.432 AC: 65623 AN: 152028 Hom.: 15147 Cov.: 32 AF XY: 0.434 AC XY: 32231 AN XY: 74310

African (AFR) AF: 0.257 AC: 10672 AN: 41452

American (AMR) AF: 0.475 AC: 7255 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.440 AC: 1527 AN: 3470

East Asian (EAS) AF: 0.343 AC: 1774 AN: 5172

South Asian (SAS) AF: 0.611 AC: 2944 AN: 4818

European-Finnish (FIN) AF: 0.501 AC: 5289 AN: 10558

Middle Eastern (MID) AF: 0.548 AC: 161 AN: 294

European-Non Finnish (NFE) AF: 0.508 AC: 34531 AN: 67964

Other (OTH) AF: 0.466 AC: 983 AN: 2110

Alfa AF: 0.331 Hom.: 1062

Bravo AF: 0.422

Asia WGS AF: 0.473 AC: 1644 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	4.3
DANN	Benign	0.75
PhyloP100		-0.092
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs6668576; hg19: chr1-160317021;