Variant 19-3192626-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_020170.4(NCLN):c.341G>A(p.Arg114Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000821 in 1,582,960 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000084 ( 0 hom. )

Consequence

NCLN
NM_020170.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.33

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 Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.03371054).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NCLN	NM_020170.4 linkuse as main transcript	c.341G>A	p.Arg114Lys	missense_variant	2/15	ENST00000246117.9	NP_064555.2	Q969V3-1
NCLN	NM_001321463.2 linkuse as main transcript	c.341G>A	p.Arg114Lys	missense_variant	2/15		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.341G>A	p.Arg114Lys	missense_variant	2/15	1	NM_020170.4	ENSP00000246117.3	Q969V3-1
NCLN	ENST00000590671.5 linkuse as main transcript	c.119G>A	p.Arg40Lys	missense_variant	2/15	2		ENSP00000466678.1	K7EMW4
NCLN	ENST00000588428.5 linkuse as main transcript	c.185-3557G>A		intron_variant		5		ENSP00000467011.1	K7ENM2

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152252

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000451

AC:

AN:

221916

Hom.:

AF XY:

0.0000325

AC XY:

AN XY:

123166

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000330

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:

0.00000839

AC:

AN:

1430708

Hom.:

Cov.:

AF XY:

0.00000565

AC XY:

AN XY:

708422

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000293

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

AF:

0.00000657

AC:

AN:

152252

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74380

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ExAC

AF:

0.0000501

AC:

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

Jan 19, 2024

The c.341G>A (p.R114K) alteration is located in exon 2 (coding exon 2) of the NCLN gene. This alteration results from a G to A substitution at nucleotide position 341, causing the arginine (R) at amino acid position 114 to be replaced by a lysine (K). 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

Benign

0.080

BayesDel_addAF

Benign

-0.53

BayesDel_noAF

Benign

-0.68

CADD

Benign

DANN

Benign

0.64

DEOGEN2

Benign

0.010

.;T

Eigen

Benign

-1.0

Eigen_PC

Benign

-0.98

FATHMM_MKL

Benign

0.074

LIST_S2

Benign

0.76

T;T

M_CAP

Benign

0.011

MetaRNN

Benign

0.034

T;T

MetaSVM

Benign

-0.99

MutationAssessor

Benign

0.10

.;N

PrimateAI

Benign

0.47

PROVEAN

Benign

0.13

.;N

REVEL

Benign

0.026

Sift

Benign

0.74

.;T

Sift4G

Benign

0.85

T;T

Polyphen

0.0

.;B

Vest4

0.28

MutPred

0.43

.;Gain of ubiquitination at R114 (P = 0.0267);

MVP

0.068

MPC

0.51

ClinPred

0.016

GERP RS

0.046

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.066

gMVP

0.25

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