1-160347594-G-C

Position:

• chr1-160347594-G-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_015331.3(NCSTN):​c.191-1405G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.967 in 152,266 control chromosomes in the GnomAD database, including 71,214 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 0.97 (71214 hom., cov: 31)
• Consequence: NCSTN NM_015331.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0470

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]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.982 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NCSTN	NM_015331.3	c.191-1405G>C		intron_variant		ENST00000294785.10	NP_056146.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NCSTN	ENST00000294785.10	c.191-1405G>C		intron_variant		1	NM_015331.3	ENSP00000294785	P1

Frequencies

GnomAD3 genomes AF: 0.967 AC: 147104 AN: 152148 Hom.: 71152 Cov.: 31

Gnomad AFR AF: 0.990

Gnomad AMI AF: 0.996

Gnomad AMR AF: 0.979

Gnomad ASJ AF: 0.978

Gnomad EAS AF: 0.998

Gnomad SAS AF: 0.952

Gnomad FIN AF: 0.973

Gnomad MID AF: 0.978

Gnomad NFE AF: 0.946

Gnomad OTH AF: 0.973

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

GnomAD4 genome AF: 0.967 AC: 147225 AN: 152266 Hom.: 71214 Cov.: 31 AF XY: 0.969 AC XY: 72116 AN XY: 74456

Gnomad4 AFR AF: 0.990

Gnomad4 AMR AF: 0.979

Gnomad4 ASJ AF: 0.978

Gnomad4 EAS AF: 0.999

Gnomad4 SAS AF: 0.953

Gnomad4 FIN AF: 0.973

Gnomad4 NFE AF: 0.946

Gnomad4 OTH AF: 0.973

Alfa AF: 0.952 Hom.: 8565

Bravo AF: 0.971

Asia WGS AF: 0.977 AC: 3400 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	8.3
DANN	Benign	0.78

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

Other links and lift over

dbSNP: rs2038781; hg19: chr1-160317384;