16-23690904-T-A

Position:

• chr16-23690904-T-A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_033266.4(ERN2):​c.2708A>T​(p.Glu903Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic 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: 7.92

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_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.94

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ERN2	NM_033266.4	c.2708A>T	p.Glu903Val	missense_variant	22/22	ENST00000256797.9	NP_150296.4
ERN2	NM_001308220.2	c.2552A>T	p.Glu851Val	missense_variant	21/21		NP_001295149.2
ERN2	XM_047433506.1	c.2276A>T	p.Glu759Val	missense_variant	19/19		XP_047289462.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ERN2	ENST00000256797.9	c.2708A>T	p.Glu903Val	missense_variant	22/22	1	NM_033266.4	ENSP00000256797	P2
ERN2	ENST00000457008.6	c.2552A>T	p.Glu851Val	missense_variant	21/21	1		ENSP00000413812	A2
ERN2	ENST00000562458.2	c.*421A>T		3_prime_UTR_variant, NMD_transcript_variant	5/5	3		ENSP00000456866

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

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 10, 2022

The c.2708A>T (p.N903I) alteration is located in exon 21 (coding exon 21) of the ERN2 gene. This alteration results from a A to T substitution at nucleotide position 2708, causing the asparagine (N) at amino acid position 903 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	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.080
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.54	.;D
Eigen	Pathogenic	0.71
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.89	D;D
M_CAP	Benign	0.066	D
MetaRNN	Pathogenic	0.94	D;D
MetaSVM	Benign	-0.42	T
MutationAssessor	Pathogenic	3.0	.;M
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.57	T
PROVEAN	Pathogenic	-6.8	D;.
REVEL	Uncertain	0.41
Sift	Pathogenic	0.0	D;.
Sift4G	Pathogenic	0.0	D;D
Polyphen		0.93	P;.
Vest4		0.59
MutPred		0.80		Loss of disorder (P = 0.0186);.;
MVP		0.71
MPC		0.59
ClinPred		1.0	D
GERP RS		5.2
Varity_R		0.27
gMVP		0.69

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: chr16-23702225;