16-23695253-C-T

Variant names:

• chr16-23695253-C-T
• NM_033266.4:c.1747G>A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_033266.4(ERN2):​c.1747G>A​(p.Gly583Arg) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ERN2 NM_033266.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.81

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ERN2	NM_033266.4	c.1747G>A	p.Gly583Arg	missense_variant	Exon 15 of 22	ENST00000256797.9	NP_150296.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ERN2	ENST00000256797.9	c.1747G>A	p.Gly583Arg	missense_variant	Exon 15 of 22	1	NM_033266.4	ENSP00000256797.5
ERN2	ENST00000457008.6	c.1591G>A	p.Gly531Arg	missense_variant	Exon 14 of 21	1		ENSP00000413812.2
ERN2	ENST00000562562.1	n.*1711G>A		non_coding_transcript_exon_variant	Exon 15 of 16	5		ENSP00000457361.1
ERN2	ENST00000562562.1	n.*1711G>A		3_prime_UTR_variant	Exon 15 of 16	5		ENSP00000457361.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Aug 14, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1747G>A (p.V583I) alteration is located in exon 14 (coding exon 14) of the ERN2 gene. This alteration results from a G to A substitution at nucleotide position 1747, causing the valine (V) at amino acid position 583 to be replaced by an isoleucine (I). 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	0.34
BayesDel_addAF	Benign	-0.019	T
BayesDel_noAF	Benign	-0.27
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.14	.;T
Eigen	Uncertain	0.34
Eigen_PC	Uncertain	0.36
FATHMM_MKL	Uncertain	0.76	D
LIST_S2	Uncertain	0.91	D;D
M_CAP	Benign	0.068	D
MetaRNN	Uncertain	0.66	D;D
MetaSVM	Benign	-0.51	T
MutationAssessor	Benign	0.88	.;L
PrimateAI	Uncertain	0.50	T
PROVEAN	Uncertain	-2.5	N;.
REVEL	Benign	0.29
Sift	Uncertain	0.010	D;.
Sift4G	Uncertain	0.0030	D;D
Polyphen		0.97	D;.
Vest4		0.48
MutPred		0.55		Gain of solvent accessibility (P = 0.0456);.;
MVP		0.89
MPC		0.48
ClinPred		0.94	D
GERP RS		3.7
Varity_R		0.21
gMVP		0.69

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.

Other links and lift over

hg19: chr16-23706574; COSMIC: COSV99891572; COSMIC: COSV99891572;