rs1085307081

chr1-160354238-C-Gchr1-160354238-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_015331.3(NCSTN):c.1300C>G(p.Arg434Gly) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,886 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R434Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: NCSTN NM_015331.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.77

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NCSTN	NM_015331.3	c.1300C>G	p.Arg434Gly	missense_variant	11/17	ENST00000294785.10
NCSTN	NM_001290184.2	c.1240C>G	p.Arg414Gly	missense_variant	12/18
NCSTN	NM_001349729.2	c.1300C>G	p.Arg434Gly	missense_variant	11/16
NCSTN	NM_001290186.2	c.886C>G	p.Arg296Gly	missense_variant	8/14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NCSTN	ENST00000294785.10	c.1300C>G	p.Arg434Gly	missense_variant	11/17	1	NM_015331.3	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251450 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135898

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461886 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727246

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.000111 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Uncertain	0.061	T
BayesDel_noAF	Benign	-0.15
Cadd	Uncertain	25
Dann	Uncertain	0.99
DEOGEN2	Uncertain	0.50	D;T
Eigen	Benign	0.13
Eigen_PC	Uncertain	0.26
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.90	D;D
M_CAP	Benign	0.033	D
MetaRNN	Uncertain	0.48	T;T
MetaSVM	Benign	-0.80	T
MutationAssessor	Uncertain	2.2	M;.
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Benign	0.25	T
PROVEAN	Uncertain	-2.5	D;D
REVEL	Uncertain	0.33
Sift	Benign	0.39	T;T
Sift4G	Benign	0.28	T;T
Polyphen		0.095	B;.
Vest4		0.44
MutPred		0.65		Loss of stability (P = 0.0166);.;
MVP		0.58
MPC		0.44
ClinPred		0.92	D
GERP RS		5.3
Varity_R		0.42
gMVP		0.76

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs1085307081; hg19: chr1-160324028; COSMIC: COSV54184491; COSMIC: COSV54184491;