17-64047941-C-A

Position:

• chr17-64047941-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The ENST00000433197.4(ERN1):​c.2446G>T​(p.Asp816Tyr) variant causes a missense change. 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: ERN1 ENST00000433197.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.75

Genes affected

ERN1 (HGNC:3449): (endoplasmic reticulum to nucleus signaling 1) This gene encodes the transmembrane protein kinase inositol-requiring enzyme 1. The encoded protein contains two functional catalytic domains, a serine/threonine-protein kinase domain and an endoribonuclease domain. This protein functions as a sensor of unfolded proteins in the endoplasmic reticulum (ER) and triggers an intracellular signaling pathway termed the unfolded protein response (UPR). The UPR is an ER stress response that is conserved from yeast to mammals and activates genes involved in degrading misfolded proteins, regulating protein synthesis and activating molecular chaperones. This protein specifically mediates the splicing and activation of the stress response transcription factor X-box binding protein 1. [provided by RefSeq, Aug 2017]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.918

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ERN1	NM_001433.5	c.2446G>T	p.Asp816Tyr	missense_variant	19/22	ENST00000433197.4	NP_001424.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ERN1	ENST00000433197.4	c.2446G>T	p.Asp816Tyr	missense_variant	19/22	1	NM_001433.5	ENSP00000401445	P1
ERN1	ENST00000680433.1	c.2446G>T	p.Asp816Tyr	missense_variant	19/20			ENSP00000506094
ERN1	ENST00000680625.1	n.2364G>T		non_coding_transcript_exon_variant	18/21

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

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

Jan 04, 2022

The c.2446G>T (p.D816Y) alteration is located in exon 19 (coding exon 19) of the ERN1 gene. This alteration results from a G to T substitution at nucleotide position 2446, causing the aspartic acid (D) at amino acid position 816 to be replaced by a tyrosine (Y). 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	0.19
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.030
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.40	T
Eigen	Uncertain	0.40
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.94	D
M_CAP	Benign	0.045	D
MetaRNN	Pathogenic	0.92	D
MetaSVM	Benign	-0.29	T
MutationAssessor	Pathogenic	3.2	M
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.53	T
PROVEAN	Pathogenic	-4.6	D
REVEL	Uncertain	0.38
Sift	Benign	0.030	D
Sift4G	Uncertain	0.011	D
Polyphen		0.39	B
Vest4		0.72
MutPred		0.81		Loss of disorder (P = 0.023);
MVP		0.71
MPC		0.64
ClinPred		0.99	D
GERP RS		5.3
Varity_R		0.84
gMVP		0.86

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: chr17-62125301; COSMIC: COSV70500586;