Variant 19-3198836-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_020170.4(NCLN):c.635G>A(p.Gly212Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000562 in 1,423,938 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000056 ( 0 hom. )

Consequence

NCLN
NM_020170.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 9.44

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:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.804

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NCLN	NM_020170.4 linkuse as main transcript	c.635G>A	p.Gly212Asp	missense_variant	5/15	ENST00000246117.9	NP_064555.2	Q969V3-1
NCLN	NM_001321463.2 linkuse as main transcript	c.635G>A	p.Gly212Asp	missense_variant	5/15		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.635G>A	p.Gly212Asp	missense_variant	5/15	1	NM_020170.4	ENSP00000246117.3	Q969V3-1
NCLN	ENST00000590671.5 linkuse as main transcript	c.413G>A	p.Gly138Asp	missense_variant	5/15	2		ENSP00000466678.1	K7EMW4
NCLN	ENST00000588428.5 linkuse as main transcript	c.299G>A	p.Gly100Asp	missense_variant	3/9	5		ENSP00000467011.1	K7ENM2
NCLN	ENST00000587740.5 linkuse as main transcript	n.-5G>A		upstream_gene_variant		1		ENSP00000466300.1	A0A0C4DGP7

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000562

AC:

AN:

1423938

Hom.:

Cov.:

AF XY:

0.00000565

AC XY:

AN XY:

708104

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

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:

0.00000731

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

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

Dec 09, 2023

The c.635G>A (p.G212D) alteration is located in exon 5 (coding exon 5) of the NCLN gene. This alteration results from a G to A substitution at nucleotide position 635, causing the glycine (G) at amino acid position 212 to be replaced by an aspartic acid (D). 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

0.55

BayesDel_addAF

Uncertain

0.13

BayesDel_noAF

Uncertain

-0.050

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.21

.;T;.

Eigen

Uncertain

0.68

Eigen_PC

Uncertain

0.63

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.94

D;D;D

M_CAP

Uncertain

0.15

MetaRNN

Pathogenic

0.80

D;D;D

MetaSVM

Uncertain

-0.26

MutationAssessor

Uncertain

2.4

.;M;.

PrimateAI

Pathogenic

0.81

PROVEAN

Pathogenic

-4.5

.;D;.

REVEL

Uncertain

0.47

Sift

Uncertain

0.0020

.;D;.

Sift4G

Uncertain

0.0060

D;D;T

Polyphen

1.0

.;D;.

Vest4

0.75

MutPred

0.36

.;Loss of methylation at R207 (P = 0.0725);.;

MVP

0.53

MPC

1.6

ClinPred

1.0

GERP RS

4.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.8

Varity_R

0.68

gMVP

0.83

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

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over