16-23690838-C-T

Variant names:

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_033266.4(ERN2):c.2774G>A(p.Gly925Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000139 in 1,610,748 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000072 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00015 ( 0 hom. )

Consequence

ERN2
NM_033266.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.916

Variant links:

Genes affected

ERN2 (HGNC:16942): (endoplasmic reticulum to nucleus signaling 2) Enables several functions, including ATP binding activity; magnesium ion binding activity; and protein serine/threonine kinase activity. Involved in several processes, including apoptotic chromosome condensation; negative regulation of transcription, DNA-templated; and rRNA catabolic process. Predicted to be located in endoplasmic reticulum membrane and endoplasmic reticulum quality control compartment. Predicted to be integral component of membrane. Predicted to be part of IRE1-TRAF2-ASK1 complex. [provided by Alliance of Genome Resources, Apr 2022]

ERN2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.10207397).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ERN2	NM_033266.4 link	c.2774G>A	p.Gly925Glu	missense_variant	Exon 22 of 22	ENST00000256797.9	NP_150296.4	Q76MJ5A5YM46A5YM65
ERN2	NM_001308220.2 link	c.2618G>A	p.Gly873Glu	missense_variant	Exon 21 of 21		NP_001295149.2	Q76MJ5A5YM46E7ETG2A5YM65
ERN2	XM_047433506.1 link	c.2342G>A	p.Gly781Glu	missense_variant	Exon 19 of 19		XP_047289462.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
ERN2	ENST00000256797.9 link	c.2774G>A	p.Gly925Glu	missense_variant	Exon 22 of 22	1	NM_033266.4	ENSP00000256797.5	Q76MJ5
ERN2	ENST00000457008.6 link	c.2618G>A	p.Gly873Glu	missense_variant	Exon 21 of 21	1		ENSP00000413812.2	E7ETG2
ERN2	ENST00000562458.2 link	n.*487G>A		non_coding_transcript_exon_variant	Exon 5 of 5	3		ENSP00000456866.2	H3BSU1
ERN2	ENST00000562458.2 link	n.*487G>A		3_prime_UTR_variant	Exon 5 of 5	3		ENSP00000456866.2	H3BSU1

Frequencies

GnomAD3 genomes

AF:

0.0000723

AC:

AN:

152226

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

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:

0.000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000567

AC:

AN:

247004

Hom.:

AF XY:

0.0000598

AC XY:

AN XY:

133826

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

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:

0.000125

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000146

AC:

213

AN:

1458522

Hom.:

Cov.:

AF XY:

0.000145

AC XY:

105

AN XY:

725678

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:

0.000183

Gnomad4 OTH exome

AF:

0.000166

GnomAD4 genome

AF:

0.0000723

AC:

AN:

152226

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74358

show subpopulations

Gnomad4 AFR

AF:

0.0000241

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:

0.000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000145

Hom.:

Bravo

AF:

0.0000680

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.0000330

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.000178

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Dec 05, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2774G>A (p.G925D) alteration is located in exon 22 (coding exon 22) of the ERN2 gene. This alteration results from a G to A substitution at nucleotide position 2774, causing the glycine (G) at amino acid position 925 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

Benign

0.076

BayesDel_addAF

Benign

-0.21

BayesDel_noAF

Benign

-0.32

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.040

.;T

Eigen

Benign

-0.37

Eigen_PC

Benign

-0.27

FATHMM_MKL

Benign

0.62

LIST_S2

Benign

0.29

T;T

M_CAP

Benign

0.017

MetaRNN

Benign

0.10

T;T

MetaSVM

Benign

-0.99

MutationAssessor

Benign

1.5

.;L

PrimateAI

Uncertain

0.60

PROVEAN

Benign

-0.19

N;N

REVEL

Benign

0.11

Sift

Pathogenic

0.0

D;T

Sift4G

Pathogenic

0.0

D;D

Polyphen

0.44

B;.

Vest4

0.078

MVP

0.68

MPC

0.71

ClinPred

0.27

GERP RS

2.7

Varity_R

0.069

gMVP

0.47

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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