rs5370

Variant names:

• chr6-12296022-G-T
• rs5370
• NM_001955.5:c.594G>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001955.5(EDN1):​c.594G>T​(p.Lys198Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.226 in 1,613,552 control chromosomes in the GnomAD database, including 43,252 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.21 (3521 hom., cov: 32)
  • Exomes 𝑓: 0.23 (39731 hom.)
• Consequence: EDN1 NM_001955.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.0700
• Publications: 270 publications found

Genes affected

EDN1 (HGNC:3176): (endothelin 1) This gene encodes a preproprotein that is proteolytically processed to generate a secreted peptide that belongs to the endothelin/sarafotoxin family. This peptide is a potent vasoconstrictor and its cognate receptors are therapeutic targets in the treatment of pulmonary arterial hypertension. Aberrant expression of this gene may promote tumorigenesis. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Oct 2015]

EDN1 Gene-Disease associations (from GenCC):

• question mark ears, isolated

  Inheritance: AD Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), G2P
• auriculocondylar syndrome 3

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• auriculocondylar syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000302734 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.002188623).
• BP6: Variant 6-12296022-G-T is Benign according to our data. Variant chr6-12296022-G-T is described in ClinVar as Benign. ClinVar VariationId is 16652.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.385 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001955.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EDN1	NM_001955.5	MANE Select	c.594G>T	p.Lys198Asn	missense	Exon 5 of 5	NP_001946.3
	EDN1	NM_001416563.1		c.594G>T	p.Lys198Asn	missense	Exon 6 of 6	NP_001403492.1	Q6FH53
	EDN1	NM_001416564.1		c.594G>T	p.Lys198Asn	missense	Exon 6 of 6	NP_001403493.1	Q6FH53

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EDN1	ENST00000379375.6	TSL:1 MANE Select	c.594G>T	p.Lys198Asn	missense	Exon 5 of 5	ENSP00000368683.5	P05305
	EDN1	ENST00000877370.1		c.618G>T	p.Lys206Asn	missense	Exon 5 of 5	ENSP00000547429.1
	EDN1	ENST00000971811.1		c.618G>T	p.Lys206Asn	missense	Exon 7 of 7	ENSP00000641870.1

Frequencies

GnomAD3 genomes AF: 0.212 AC: 32244 AN: 151840 Hom.: 3523 Cov.: 32

Gnomad AFR AF: 0.194

Gnomad AMI AF: 0.214

Gnomad AMR AF: 0.174

Gnomad ASJ AF: 0.211

Gnomad EAS AF: 0.290

Gnomad SAS AF: 0.399

Gnomad FIN AF: 0.186

Gnomad MID AF: 0.193

Gnomad NFE AF: 0.218

Gnomad OTH AF: 0.200

GnomAD2 exomes AF: 0.229 AC: 57654 AN: 251452 AF XY: 0.239

Gnomad AFR exome AF: 0.190

Gnomad AMR exome AF: 0.148

Gnomad ASJ exome AF: 0.211

Gnomad EAS exome AF: 0.281

Gnomad FIN exome AF: 0.190

Gnomad NFE exome AF: 0.215

Gnomad OTH exome AF: 0.219

GnomAD4 exome AF: 0.227 AC: 331748 AN: 1461594 Hom.: 39731 Cov.: 33 AF XY: 0.232 AC XY: 168849 AN XY: 727110

African (AFR) AF: 0.188 AC: 6299 AN: 33478

American (AMR) AF: 0.149 AC: 6644 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.212 AC: 5551 AN: 26136

East Asian (EAS) AF: 0.283 AC: 11251 AN: 39690

South Asian (SAS) AF: 0.399 AC: 34382 AN: 86248

European-Finnish (FIN) AF: 0.189 AC: 10094 AN: 53390

Middle Eastern (MID) AF: 0.245 AC: 1413 AN: 5766

European-Non Finnish (NFE) AF: 0.218 AC: 241961 AN: 1111792

Other (OTH) AF: 0.234 AC: 14153 AN: 60374

GnomAD4 genome AF: 0.212 AC: 32242 AN: 151958 Hom.: 3521 Cov.: 32 AF XY: 0.214 AC XY: 15904 AN XY: 74260

African (AFR) AF: 0.194 AC: 8023 AN: 41442

American (AMR) AF: 0.173 AC: 2648 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.211 AC: 731 AN: 3470

East Asian (EAS) AF: 0.290 AC: 1491 AN: 5144

South Asian (SAS) AF: 0.400 AC: 1925 AN: 4818

European-Finnish (FIN) AF: 0.186 AC: 1960 AN: 10518

Middle Eastern (MID) AF: 0.187 AC: 55 AN: 294

European-Non Finnish (NFE) AF: 0.218 AC: 14796 AN: 67986

Other (OTH) AF: 0.198 AC: 418 AN: 2110

Alfa AF: 0.217 Hom.: 18166

Bravo AF: 0.207

TwinsUK AF: 0.217 AC: 804

ALSPAC AF: 0.219 AC: 845

ESP6500AA AF: 0.196 AC: 865

ESP6500EA AF: 0.211 AC: 1817

ExAC AF: 0.234 AC: 28467

Asia WGS AF: 0.309 AC: 1072 AN: 3478

EpiCase AF: 0.217

EpiControl AF: 0.216

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Auriculocondylar syndrome 3 (1)
-	-	1	High density lipoprotein cholesterol level quantitative trait locus 7 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	11
DANN	Benign	0.97
DEOGEN2	Uncertain	0.42	T
Eigen	Benign	-0.66
Eigen_PC	Benign	-0.71
FATHMM_MKL	Benign	0.21	N
LIST_S2	Benign	0.24	T
MetaRNN	Benign	0.0022	T
MetaSVM	Benign	-0.89	T
MutationAssessor	Benign	1.3	L
PhyloP100		0.070
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-0.89	N
REVEL	Benign	0.16
Sift	Benign	0.12	T
Sift4G	Uncertain	0.025	D
Polyphen		0.45	P
Vest4		0.037
MutPred		0.078		Loss of methylation at K198 (P = 0.0204)
MPC		0.26
ClinPred		0.0022	T
GERP RS		2.2
Varity_R		0.10
gMVP		0.054
Mutation Taster		=87/13	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: rs5370; hg19: chr6-12296255; COSMIC: COSV65080553;