chr17-64049624-C-T

Position:

• chr17-64049624-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001433.5(ERN1):​c.2254-422G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.588 in 152,054 control chromosomes in the GnomAD database, including 30,333 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.59 (30333 hom., cov: 32)
• Consequence: ERN1 NM_001433.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.117

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 Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.754 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ERN1	NM_001433.5	c.2254-422G>A		intron_variant		ENST00000433197.4	NP_001424.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ERN1	ENST00000433197.4	c.2254-422G>A		intron_variant		1	NM_001433.5	ENSP00000401445	P1
ERN1	ENST00000680433.1	c.2254-422G>A		intron_variant				ENSP00000506094
ERN1	ENST00000680625.1	n.2172-422G>A		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.588 AC: 89361 AN: 151936 Hom.: 30330 Cov.: 32

Gnomad AFR AF: 0.229

Gnomad AMI AF: 0.700

Gnomad AMR AF: 0.611

Gnomad ASJ AF: 0.591

Gnomad EAS AF: 0.645

Gnomad SAS AF: 0.765

Gnomad FIN AF: 0.736

Gnomad MID AF: 0.680

Gnomad NFE AF: 0.759

Gnomad OTH AF: 0.605

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.588 AC: 89376 AN: 152054 Hom.: 30333 Cov.: 32 AF XY: 0.590 AC XY: 43810 AN XY: 74316

Gnomad4 AFR AF: 0.228

Gnomad4 AMR AF: 0.611

Gnomad4 ASJ AF: 0.591

Gnomad4 EAS AF: 0.645

Gnomad4 SAS AF: 0.767

Gnomad4 FIN AF: 0.736

Gnomad4 NFE AF: 0.759

Gnomad4 OTH AF: 0.607

Alfa AF: 0.666 Hom.: 4626

Bravo AF: 0.559

Asia WGS AF: 0.708 AC: 2463 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	3.0
DANN	Benign	0.77

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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

Other links and lift over

dbSNP: rs77684; hg19: chr17-62126984;