NM_015331.3:c.61C>T

Variant names:

• chr1-160343457-C-T
• rs199694056
• NM_015331.3:c.61C>T

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 0P and 15B. BP4_Strong BP6_Moderate BP7 BS1 BS2

The NM_015331.3(NCSTN):​c.61C>T​(p.Leu21Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000158 in 1,458,914 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.000016 (0 hom.)
• Consequence: NCSTN NM_015331.3 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.371
• Publications: 1 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]

COPA (HGNC:2230): (COPI coat complex subunit alpha) In eukaryotic cells, protein transport between the endoplasmic reticulum and Golgi compartments is mediated in part by non-clathrin-coated vesicular coat proteins (COPs). Seven coat proteins have been identified, and they represent subunits of a complex known as coatomer. The subunits are designated alpha-COP, beta-COP, beta-prime-COP, gamma-COP, delta-COP, epsilon-COP, and zeta-COP. The alpha-COP, encoded by COPA, shares high sequence similarity with RET1P, the alpha subunit of the coatomer complex in yeast. Also, the N-terminal 25 amino acids of alpha-COP encode the bioactive peptide, xenin, which stimulates exocrine pancreatic secretion and may act as a gastrointestinal hormone. Alternative splicing results in multiple splice forms encoding distinct isoforms. [provided by RefSeq, Jul 2008]

COPA Gene-Disease associations (from GenCC):

• autoimmune interstitial lung disease-arthritis syndrome

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.63).
• BP6: Variant 1-160343457-C-T is Benign according to our data. Variant chr1-160343457-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 1566588.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=0.371 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. GnomAdExome4 allele frequency = 0.0000158 (23/1458914) while in subpopulation SAS AF = 0.000258 (22/85424). AF 95% confidence interval is 0.000174. There are 0 homozygotes in GnomAdExome4. There are 13 alleles in the male GnomAdExome4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High AC in GnomAdExome4 at 23 AD gene.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NCSTN	NM_015331.3	MANE Select	c.61C>T	p.Leu21Leu	synonymous	Exon 1 of 17	NP_056146.1	Q92542-1
	NCSTN	NM_001290184.2		c.-139C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 18	NP_001277113.1	Q92542-2
	NCSTN	NM_001349729.2		c.61C>T	p.Leu21Leu	synonymous	Exon 1 of 16	NP_001336658.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NCSTN	ENST00000294785.10	TSL:1 MANE Select	c.61C>T	p.Leu21Leu	synonymous	Exon 1 of 17	ENSP00000294785.5	Q92542-1
	NCSTN	ENST00000368063.6	TSL:1	n.61C>T		non_coding_transcript_exon	Exon 1 of 18	ENSP00000357042.2	A0A2U3TZL9
	NCSTN	ENST00000913597.1		c.61C>T	p.Leu21Leu	synonymous	Exon 1 of 18	ENSP00000583656.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD2 exomes AF: 0.0000370 AC: 9 AN: 243220 AF XY: 0.0000457

Gnomad AFR exome AF: 0.00

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: 0.0000158 AC: 23 AN: 1458914 Hom.: 0 Cov.: 31 AF XY: 0.0000179 AC XY: 13 AN XY: 725396

African (AFR) AF: 0.0000299 AC: 1 AN: 33458

American (AMR) AF: 0.00 AC: 0 AN: 44220

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25860

East Asian (EAS) AF: 0.00 AC: 0 AN: 39596

South Asian (SAS) AF: 0.000258 AC: 22 AN: 85424

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53248

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5740

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111126

Other (OTH) AF: 0.00 AC: 0 AN: 60242

GnomAD4 genome Cov.: 31

Alfa AF: 0.0000508 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.63
CADD	Benign	9.9
DANN	Benign	0.87
PhyloP100		0.37
PromoterAI		-0.025	Neutral
Mutation Taster		=299/1	polymorphism

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: rs199694056; hg19: chr1-160313247; COSMIC: COSV54109186; COSMIC: COSV54109186;