16-23691019-C-T

Variant names:

• chr16-23691019-C-T
• NM_033266.4:c.2593G>A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_033266.4(ERN2):​c.2593G>A​(p.Val865Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: ERN2 NM_033266.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.0320

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.048953474).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ERN2	NM_033266.4	c.2593G>A	p.Val865Ile	missense_variant	Exon 22 of 22	ENST00000256797.9	NP_150296.4
ERN2	NM_001308220.2	c.2437G>A	p.Val813Ile	missense_variant	Exon 21 of 21		NP_001295149.2
ERN2	XM_047433506.1	c.2161G>A	p.Val721Ile	missense_variant	Exon 19 of 19		XP_047289462.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ERN2	ENST00000256797.9	c.2593G>A	p.Val865Ile	missense_variant	Exon 22 of 22	1	NM_033266.4	ENSP00000256797.5
ERN2	ENST00000457008.6	c.2437G>A	p.Val813Ile	missense_variant	Exon 21 of 21	1		ENSP00000413812.2
ERN2	ENST00000562458.2	n.*306G>A		non_coding_transcript_exon_variant	Exon 5 of 5	3		ENSP00000456866.2
ERN2	ENST00000562458.2	n.*306G>A		3_prime_UTR_variant	Exon 5 of 5	3		ENSP00000456866.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 23, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2593G>A (p.A865T) alteration is located in exon 20 (coding exon 20) of the ERN2 gene. This alteration results from a G to A substitution at nucleotide position 2593, causing the alanine (A) at amino acid position 865 to be replaced by a threonine (T). 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	0.090
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.68
CADD	Benign	11
DANN	Benign	0.95
DEOGEN2	Benign	0.066	.;T
Eigen	Benign	-1.0
Eigen_PC	Benign	-0.99
FATHMM_MKL	Benign	0.47	N
LIST_S2	Benign	0.62	T;T
M_CAP	Benign	0.0069	T
MetaRNN	Benign	0.049	T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	-0.34	.;N
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-0.76	N;.
REVEL	Benign	0.012
Sift	Benign	0.15	T;.
Sift4G	Benign	0.18	T;T
Polyphen		0.061	B;.
Vest4		0.085
MutPred		0.37		Loss of MoRF binding (P = 0.112);.;
MVP		0.27
MPC		0.13
ClinPred		0.11	T
GERP RS		0.94
Varity_R		0.018
gMVP		0.27

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr16-23702340;