chr1-160354238-C-G

Variant names:

• chr1-160354238-C-G
• rs1085307081
• NM_015331.3:c.1300C>G

Variant summary

Our verdict is Uncertain significance. The variant received 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
• Publications: 7 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: Uncertain_significance. The variant received 2 ACMG points.

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

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.1300C>G	p.Arg434Gly	missense	Exon 11 of 17	NP_056146.1
	NCSTN	NM_001290184.2		c.1240C>G	p.Arg414Gly	missense	Exon 12 of 18	NP_001277113.1
	NCSTN	NM_001349729.2		c.1300C>G	p.Arg434Gly	missense	Exon 11 of 16	NP_001336658.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NCSTN	ENST00000294785.10	TSL:1 MANE Select	c.1300C>G	p.Arg434Gly	missense	Exon 11 of 17	ENSP00000294785.5
	NCSTN	ENST00000368063.6	TSL:1	n.*1229C>G		non_coding_transcript_exon	Exon 12 of 18	ENSP00000357042.2
	NCSTN	ENST00000368063.6	TSL:1	n.*1229C>G		3_prime_UTR	Exon 12 of 18	ENSP00000357042.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251450 AF XY: 0.00

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 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

African (AFR) AF: 0.0000299 AC: 1 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53414

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1112010

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 32

Alfa AF: 0.000111 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

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
Eigen	Benign	0.13
Eigen_PC	Uncertain	0.26
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.90	D
M_CAP	Benign	0.033	D
MetaRNN	Uncertain	0.48	T
MetaSVM	Benign	-0.80	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		3.8
PrimateAI	Benign	0.25	T
PROVEAN	Uncertain	-2.5	D
REVEL	Uncertain	0.33
Sift	Benign	0.39	T
Sift4G	Benign	0.28	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
Mutation Taster		=60/40	polymorphism

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

Other links and lift over

dbSNP: rs1085307081; hg19: chr1-160324028; COSMIC: COSV54184491; COSMIC: COSV54184491;