Variant 19-3201595-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_020170.4(NCLN):c.769C>T(p.Arg257Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000213 in 1,501,778 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 0.000014 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000022 ( 0 hom. )

Consequence

NCLN
NM_020170.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.692

Variant links:

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]

NCLN links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.423481).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NCLN	NM_020170.4 linkuse as main transcript	c.769C>T	p.Arg257Trp	missense_variant	6/15	ENST00000246117.9	NP_064555.2	Q969V3-1
NCLN	NM_001321463.2 linkuse as main transcript	c.769C>T	p.Arg257Trp	missense_variant	6/15		NP_001308392.1	Q969V3-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
NCLN	ENST00000246117.9 linkuse as main transcript	c.769C>T	p.Arg257Trp	missense_variant	6/15	1	NM_020170.4	ENSP00000246117.3	Q969V3-1
NCLN	ENST00000587740.5 linkuse as main transcript	n.130C>T		non_coding_transcript_exon_variant	2/12	1		ENSP00000466300.1	A0A0C4DGP7
NCLN	ENST00000590671.5 linkuse as main transcript	c.547C>T	p.Arg183Trp	missense_variant	6/15	2		ENSP00000466678.1	K7EMW4
NCLN	ENST00000588428.5 linkuse as main transcript	c.433C>T	p.Arg145Trp	missense_variant	4/9	5		ENSP00000467011.1	K7ENM2

Frequencies

GnomAD3 genomes

AF:

0.0000135

AC:

AN:

148062

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000248

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000150

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000405

AC:

AN:

173042

Hom.:

AF XY:

0.0000212

AC XY:

AN XY:

94220

show subpopulations

Gnomad AFR exome

AF:

0.0000922

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000140

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000135

Gnomad OTH exome

AF:

0.000632

GnomAD4 exome

AF:

0.0000222

AC:

AN:

1353716

Hom.:

Cov.:

AF XY:

0.0000164

AC XY:

AN XY:

670242

show subpopulations

Gnomad4 AFR exome

AF:

0.0000647

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000119

Gnomad4 SAS exome

AF:

0.0000374

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000132

Gnomad4 OTH exome

AF:

0.000109

GnomAD4 genome

AF:

0.0000135

AC:

AN:

148062

Hom.:

Cov.:

AF XY:

0.0000138

AC XY:

AN XY:

72230

show subpopulations

Gnomad4 AFR

AF:

0.0000248

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000150

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000264

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 08, 2024

The c.769C>T (p.R257W) alteration is located in exon 6 (coding exon 6) of the NCLN gene. This alteration results from a C to T substitution at nucleotide position 769, causing the arginine (R) at amino acid position 257 to be replaced by a tryptophan (W). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.37

BayesDel_addAF

Benign

-0.065

BayesDel_noAF

Benign

-0.33

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.21

.;T;.

Eigen

Benign

-0.20

Eigen_PC

Benign

-0.42

FATHMM_MKL

Benign

0.16

LIST_S2

Pathogenic

0.99

D;D;D

M_CAP

Uncertain

0.12

MetaRNN

Benign

0.42

T;T;T

MetaSVM

Benign

-0.47

MutationAssessor

Uncertain

2.7

.;M;.

PrimateAI

Pathogenic

0.81

PROVEAN

Pathogenic

-5.2

.;D;.

REVEL

Uncertain

0.30

Sift

Uncertain

0.0080

.;D;.

Sift4G

Uncertain

0.0080

D;D;D

Polyphen

1.0

.;D;.

Vest4

0.74

MVP

0.24

MPC

1.4

ClinPred

0.87

GERP RS

-0.55

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.35

gMVP

0.87

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over