rs1057519322

Positions:

• chr19-3193404-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP5

The NM_020170.4(NCLN):​c.496C>T​(p.Gln166Ter) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: NCLN NM_020170.4 stop_gained
• Clinical Significance: Likely pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 7.46

Genes affected

NCLN (HGNC:26923): (nicalin) Enables ribosome binding activity. Involved in protein stabilization; regulation of protein complex stability; and regulation of protein-containing complex assembly. Located in endoplasmic reticulum membrane. Part of protein-containing complex. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 19-3193404-C-T is Pathogenic according to our data. Variant chr19-3193404-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 375276.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NCLN	NM_020170.4	c.496C>T	p.Gln166Ter	stop_gained	3/15	ENST00000246117.9	NP_064555.2
NCLN	NM_001321463.2	c.496C>T	p.Gln166Ter	stop_gained	3/15		NP_001308392.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NCLN	ENST00000246117.9	c.496C>T	p.Gln166Ter	stop_gained	3/15	1	NM_020170.4	ENSP00000246117	P1
NCLN	ENST00000590671.5	c.274C>T	p.Gln92Ter	stop_gained	3/15	2		ENSP00000466678
NCLN	ENST00000588428.5	c.185-2779C>T		intron_variant		5		ENSP00000467011

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Hirschsprung disease, susceptibility to, 1 Pathogenic:1

Likely pathogenic, no assertion criteria provided

in vivo

Centre for Genomic Sciences, University of Hong Kong

Sep 26, 2016

Nonsense mutation -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.62	D
BayesDel_noAF	Pathogenic	0.55
CADD	Pathogenic	41
DANN	Uncertain	1.0
Eigen	Pathogenic	0.79
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Uncertain	0.93	D
MutationTaster	Benign	1.0	A;A
Vest4		0.40
GERP RS		4.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs1057519322; hg19: chr19-3193402; COSMIC: COSV55743233;