rs196912

Variant names:

• chr17-64044120-T-C
• rs196912
• NM_001433.5:c.2802A>G

Your query was ambiguous. Multiple possible variants found:

• chr17-64044120-T-C
• chr17-64044120-T-G

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP7 BA1

The NM_001433.5(ERN1):​c.2802A>G​(p.Thr934Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.725 in 1,609,910 control chromosomes in the GnomAD database, including 433,215 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 0.61 (31175 hom., cov: 30)
  • Exomes 𝑓: 0.74 (402040 hom.)
• Consequence: ERN1 NM_001433.5 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -4.37
• Publications: 23 publications found

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

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP7: Synonymous conserved (PhyloP=-4.37 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.754 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001433.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ERN1	NM_001433.5	MANE Select	c.2802A>G	p.Thr934Thr	synonymous	Exon 22 of 22	NP_001424.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ERN1	ENST00000433197.4	TSL:1 MANE Select	c.2802A>G	p.Thr934Thr	synonymous	Exon 22 of 22	ENSP00000401445.2
	ERN1	ENST00000680625.1		n.2720A>G		non_coding_transcript_exon	Exon 21 of 21
	ERN1	ENST00000680433.1		c.*1174A>G		3_prime_UTR	Exon 20 of 20	ENSP00000506094.1

Frequencies

GnomAD3 genomes AF: 0.607 AC: 92193 AN: 151798 Hom.: 31174 Cov.: 30

Gnomad AFR AF: 0.291

Gnomad AMI AF: 0.700

Gnomad AMR AF: 0.617

Gnomad ASJ AF: 0.599

Gnomad EAS AF: 0.667

Gnomad SAS AF: 0.765

Gnomad FIN AF: 0.737

Gnomad MID AF: 0.680

Gnomad NFE AF: 0.760

Gnomad OTH AF: 0.616

GnomAD2 exomes AF: 0.695 AC: 171012 AN: 245926 AF XY: 0.710

Gnomad AFR exome AF: 0.277

Gnomad AMR exome AF: 0.634

Gnomad ASJ exome AF: 0.587

Gnomad EAS exome AF: 0.651

Gnomad FIN exome AF: 0.749

Gnomad NFE exome AF: 0.761

Gnomad OTH exome AF: 0.704

GnomAD4 exome AF: 0.738 AC: 1075712 AN: 1457994 Hom.: 402040 Cov.: 48 AF XY: 0.741 AC XY: 536961 AN XY: 725032

African (AFR) AF: 0.274 AC: 9137 AN: 33368

American (AMR) AF: 0.636 AC: 28188 AN: 44334

Ashkenazi Jewish (ASJ) AF: 0.592 AC: 15408 AN: 26038

East Asian (EAS) AF: 0.702 AC: 27710 AN: 39492

South Asian (SAS) AF: 0.753 AC: 64578 AN: 85730

European-Finnish (FIN) AF: 0.749 AC: 39909 AN: 53250

Middle Eastern (MID) AF: 0.681 AC: 3919 AN: 5756

European-Non Finnish (NFE) AF: 0.761 AC: 844410 AN: 1109806

Other (OTH) AF: 0.705 AC: 42453 AN: 60220

GnomAD4 genome AF: 0.607 AC: 92217 AN: 151916 Hom.: 31175 Cov.: 30 AF XY: 0.608 AC XY: 45137 AN XY: 74242

African (AFR) AF: 0.291 AC: 12044 AN: 41368

American (AMR) AF: 0.617 AC: 9417 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.599 AC: 2079 AN: 3472

East Asian (EAS) AF: 0.667 AC: 3439 AN: 5156

South Asian (SAS) AF: 0.766 AC: 3694 AN: 4822

European-Finnish (FIN) AF: 0.737 AC: 7776 AN: 10556

Middle Eastern (MID) AF: 0.680 AC: 200 AN: 294

European-Non Finnish (NFE) AF: 0.760 AC: 51626 AN: 67960

Other (OTH) AF: 0.618 AC: 1305 AN: 2110

Alfa AF: 0.696 Hom.: 69505

Bravo AF: 0.580

Asia WGS AF: 0.716 AC: 2488 AN: 3478

EpiCase AF: 0.747

EpiControl AF: 0.739

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.046
DANN	Benign	0.59
PhyloP100		-4.4
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs196912; hg19: chr17-62121480; COSMIC: COSV70501012;