16-23690838-C-T

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

2
2
15

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]

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
ERN2NM_033266.4 linkc.2774G>A p.Gly925Glu missense_variant Exon 22 of 22 ENST00000256797.9 NP_150296.4 Q76MJ5A5YM46A5YM65
ERN2NM_001308220.2 linkc.2618G>A p.Gly873Glu missense_variant Exon 21 of 21 NP_001295149.2 Q76MJ5A5YM46E7ETG2A5YM65
ERN2XM_047433506.1 linkc.2342G>A p.Gly781Glu missense_variant Exon 19 of 19 XP_047289462.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
ERN2ENST00000256797.9 linkc.2774G>A p.Gly925Glu missense_variant Exon 22 of 22 1 NM_033266.4 ENSP00000256797.5 Q76MJ5
ERN2ENST00000457008.6 linkc.2618G>A p.Gly873Glu missense_variant Exon 21 of 21 1 ENSP00000413812.2 E7ETG2
ERN2ENST00000562458.2 linkn.*487G>A non_coding_transcript_exon_variant Exon 5 of 5 3 ENSP00000456866.2 H3BSU1
ERN2ENST00000562458.2 linkn.*487G>A 3_prime_UTR_variant Exon 5 of 5 3 ENSP00000456866.2 H3BSU1

Frequencies

GnomAD3 genomes
AF:
0.0000723
AC:
11
AN:
152226
Hom.:
0
Cov.:
33
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:
14
AN:
247004
Hom.:
0
AF XY:
0.0000598
AC XY:
8
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.:
0
Cov.:
33
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:
11
AN:
152226
Hom.:
0
Cov.:
33
AF XY:
0.0000269
AC XY:
2
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.:
0
Bravo
AF:
0.0000680
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000233
AC:
2
ExAC
AF:
0.0000330
AC:
4
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
T
BayesDel_noAF
Benign
-0.32
CADD
Benign
19
DANN
Uncertain
0.99
DEOGEN2
Benign
0.040
.;T
Eigen
Benign
-0.37
Eigen_PC
Benign
-0.27
FATHMM_MKL
Benign
0.62
D
LIST_S2
Benign
0.29
T;T
M_CAP
Benign
0.017
T
MetaRNN
Benign
0.10
T;T
MetaSVM
Benign
-0.99
T
MutationAssessor
Benign
1.5
.;L
PrimateAI
Uncertain
0.60
T
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
T
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.

Other links and lift over

dbSNP: rs376486441; hg19: chr16-23702159; API