Variant 16-23691422-C-T details in Genebe, Genetics Data Aggregator

Variant summary

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

The NM_033266.4(ERN2):c.2380G>A(p.Val794Ile) variant causes a missense change. The variant allele was found at a frequency of 0.0000369 in 1,598,770 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00017 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000023 ( 0 hom. )

Consequence

ERN2
NM_033266.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.86

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=0.13742667).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
ERN2	NM_033266.4 linkuse as main transcript	c.2380G>A	p.Val794Ile	missense_variant	20/22	ENST00000256797.9	NP_150296.4
ERN2	NM_001308220.2 linkuse as main transcript	c.2224G>A	p.Val742Ile	missense_variant	19/21		NP_001295149.2
ERN2	XM_047433506.1 linkuse as main transcript	c.1948G>A	p.Val650Ile	missense_variant	17/19		XP_047289462.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
ERN2	ENST00000256797.9 linkuse as main transcript	c.2380G>A	p.Val794Ile	missense_variant	20/22	1	NM_033266.4	ENSP00000256797	P2
ERN2	ENST00000457008.6 linkuse as main transcript	c.2224G>A	p.Val742Ile	missense_variant	19/21	1		ENSP00000413812	A2
ERN2	ENST00000562458.2 linkuse as main transcript	c.*93G>A		3_prime_UTR_variant, NMD_transcript_variant	3/5	3		ENSP00000456866

Frequencies

GnomAD3 genomes

AF:

0.000171

AC:

AN:

152224

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000579

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000550

AC:

AN:

236578

Hom.:

AF XY:

0.0000465

AC XY:

AN XY:

129028

show subpopulations

Gnomad AFR exome

AF:

0.000449

Gnomad AMR exome

AF:

0.0000584

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000993

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000899

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000228

AC:

AN:

1446428

Hom.:

Cov.:

AF XY:

0.0000278

AC XY:

AN XY:

719960

show subpopulations

Gnomad4 AFR exome

AF:

0.000359

Gnomad4 AMR exome

AF:

0.0000448

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000720

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.000171

AC:

AN:

152342

Hom.:

Cov.:

AF XY:

0.000148

AC XY:

AN XY:

74488

show subpopulations

Gnomad4 AFR

AF:

0.000577

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000366

Hom.:

Bravo

AF:

0.000185

ESP6500AA

AF:

0.000455

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000494

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.0000545

EpiControl

AF:

0.0000595

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 10, 2023

The c.2380G>A (p.E794K) alteration is located in exon 18 (coding exon 18) of the ERN2 gene. This alteration results from a G to A substitution at nucleotide position 2380, causing the glutamic acid (E) at amino acid position 794 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

0.12

BayesDel_addAF

Benign

-0.43

BayesDel_noAF

Benign

-0.53

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.090

.;T

Eigen

Uncertain

0.32

Eigen_PC

Uncertain

0.31

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.93

D;D

M_CAP

Benign

0.017

MetaRNN

Benign

0.14

T;T

MetaSVM

Benign

-0.57

MutationAssessor

Uncertain

2.6

.;M

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.51

PROVEAN

Benign

-0.86

N;.

REVEL

Benign

0.15

Sift

Benign

0.082

T;.

Sift4G

Benign

0.068

T;D

Polyphen

0.16

B;.

Vest4

0.27

MVP

0.65

MPC

0.16

ClinPred

0.11

GERP RS

4.7

Varity_R

0.25

gMVP

0.46

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.090

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