Variant chr19-3192659-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2BP4_StrongBP6_Moderate

The NM_020170.4(NCLN):c.374G>A(p.Arg125Gln) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.000185 in 1,549,460 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.00087 ( 1 hom., cov: 33)

Exomes 𝑓: 0.00011 ( 0 hom. )

Consequence

NCLN
NM_020170.4 missense, splice_region

Scores

Splicing: ADA: 0.0008285

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 4.81

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 -4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.00909394).

BP6

Variant 19-3192659-G-A is Benign according to our data. Variant chr19-3192659-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 757650.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NCLN	NM_020170.4 linkuse as main transcript	c.374G>A	p.Arg125Gln	missense_variant, splice_region_variant	2/15	ENST00000246117.9	NP_064555.2	Q969V3-1
NCLN	NM_001321463.2 linkuse as main transcript	c.374G>A	p.Arg125Gln	missense_variant, splice_region_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.374G>A	p.Arg125Gln	missense_variant, splice_region_variant	2/15	1	NM_020170.4	ENSP00000246117.3	Q969V3-1
NCLN	ENST00000590671.5 linkuse as main transcript	c.152G>A	p.Arg51Gln	missense_variant, splice_region_variant	2/15	2		ENSP00000466678.1	K7EMW4
NCLN	ENST00000588428.5 linkuse as main transcript	c.185-3524G>A		intron_variant		5		ENSP00000467011.1	K7ENM2

Frequencies

GnomAD3 genomes

AF:

0.000874

AC:

133

AN:

152234

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00311

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:

0.00316

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000211

AC:

AN:

184426

Hom.:

AF XY:

0.000194

AC XY:

AN XY:

102994

show subpopulations

Gnomad AFR exome

AF:

0.00248

Gnomad AMR exome

AF:

0.000206

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000708

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000547

Gnomad NFE exome

AF:

0.0000360

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000110

AC:

154

AN:

1397108

Hom.:

Cov.:

AF XY:

0.0000914

AC XY:

AN XY:

689236

show subpopulations

Gnomad4 AFR exome

AF:

0.00348

Gnomad4 AMR exome

AF:

0.000140

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000269

Gnomad4 SAS exome

AF:

0.0000254

Gnomad4 FIN exome

AF:

0.0000199

Gnomad4 NFE exome

AF:

0.0000185

Gnomad4 OTH exome

AF:

0.000226

GnomAD4 genome

AF:

0.000873

AC:

133

AN:

152352

Hom.:

Cov.:

AF XY:

0.000886

AC XY:

AN XY:

74492

show subpopulations

Gnomad4 AFR

AF:

0.00310

Gnomad4 AMR

AF:

0.0000653

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000471

Hom.:

Bravo

AF:

0.000895

ESP6500AA

AF:

0.00140

AC:

ESP6500EA

AF:

0.000119

AC:

ExAC

AF:

0.000295

AC:

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 06, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.065

BayesDel_addAF

Benign

-0.62

BayesDel_noAF

Benign

-0.67

CADD

Benign

DANN

Benign

0.72

DEOGEN2

Benign

0.010

.;T

Eigen

Benign

-0.50

Eigen_PC

Benign

-0.24

FATHMM_MKL

Uncertain

0.88

LIST_S2

Uncertain

0.93

D;D

M_CAP

Benign

0.014

MetaRNN

Benign

0.0091

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.71

.;N

PrimateAI

Benign

0.36

PROVEAN

Benign

1.1

.;N

REVEL

Benign

0.071

Sift

Benign

1.0

.;T

Sift4G

Benign

1.0

T;T

Polyphen

0.0

.;B

Vest4

0.32

MVP

0.10

MPC

0.58

ClinPred

0.031

GERP RS

4.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.7

Varity_R

0.055

gMVP

0.34

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00083

dbscSNV1_RF

Benign

0.070

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