Genetic Variant NM_001956.5:c.65-98G>A (chr1-41484301-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_001956.5(EDN2):c.65-98G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.174 in 1,458,372 control chromosomes in the GnomAD database, including 23,996 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 0.14 ( 2027 hom., cov: 34)

Exomes 𝑓: 0.18 ( 21969 hom. )

Consequence

EDN2
NM_001956.5 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -2.19

Publications

8 publications found

Variant links:

Genes affected

EDN2 (HGNC:3177): (endothelin 2) This gene encodes a member of the endothelin protein family of secretory vasoconstrictive peptides. The preproprotein is processed to a short mature form which functions as a ligand for the endothelin receptors that initiate intracellular signaling events. This gene product is involved in a wide range of biological processes, such as hypertension and ovulation. Altered expression of this gene is implicated in tumorigenesis. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Oct 2014]

EDN2 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.88).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.314 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001956.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
EDN2	NM_001956.5	MANE Select	c.65-98G>A	intron	N/A	NP_001947.1
EDN2	NM_001302269.2		c.65-98G>A	intron	N/A	NP_001289198.1
EDN2	NR_126098.2		n.147-189G>A	intron	N/A

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
EDN2	ENST00000372587.5	TSL:1 MANE Select	c.65-98G>A	intron	N/A	ENSP00000361668.4
EDN2	ENST00000490783.5	TSL:3	n.137-189G>A	intron	N/A
EDN2	ENST00000460255.1	TSL:1	n.-216G>A	upstream_gene	N/A

Frequencies

GnomAD3 genomes

AF:

0.144

AC:

21882

AN:

152064

Hom.:

2025

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0420

Gnomad AMI

AF:

0.231

Gnomad AMR

AF:

0.125

Gnomad ASJ

AF:

0.142

Gnomad EAS

AF:

0.326

Gnomad SAS

AF:

0.150

Gnomad FIN

AF:

0.223

Gnomad MID

AF:

0.104

Gnomad NFE

AF:

0.182

Gnomad OTH

AF:

0.159

GnomAD4 exome

AF:

0.178

AC:

232128

AN:

1306190

Hom.:

21969

AF XY:

0.177

AC XY:

113297

AN XY:

640542

show subpopulations

African (AFR)

AF:

0.0390

AC:

1163

AN:

29806

American (AMR)

AF:

0.0974

AC:

3188

AN:

32734

Ashkenazi Jewish (ASJ)

AF:

0.137

AC:

2940

AN:

21506

East Asian (EAS)

AF:

0.347

AC:

12378

AN:

35652

South Asian (SAS)

AF:

0.149

AC:

10406

AN:

69724

European-Finnish (FIN)

AF:

0.220

AC:

10086

AN:

45810

Middle Eastern (MID)

AF:

0.118

AC:

441

AN:

3730

European-Non Finnish (NFE)

AF:

0.180

AC:

182353

AN:

1012836

Other (OTH)

AF:

0.169

AC:

9173

AN:

54392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

9554

19109

28663

38218

47772

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

6470

12940

19410

25880

32350

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.144

AC:

21890

AN:

152182

Hom.:

2027

Cov.:

AF XY:

0.147

AC XY:

10907

AN XY:

74406

show subpopulations

African (AFR)

AF:

0.0420

AC:

1747

AN:

41558

American (AMR)

AF:

0.124

AC:

1903

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.142

AC:

493

AN:

3470

East Asian (EAS)

AF:

0.327

AC:

1684

AN:

5150

South Asian (SAS)

AF:

0.150

AC:

726

AN:

4830

European-Finnish (FIN)

AF:

0.223

AC:

2365

AN:

10586

Middle Eastern (MID)

AF:

0.105

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.182

AC:

12392

AN:

67974

Other (OTH)

AF:

0.160

AC:

338

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

959

1918

2878

3837

4796

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

252

504

756

1008

1260

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.154

Hom.:

300

Bravo

AF:

0.131

Asia WGS

AF:

0.213

AC:

742

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.88

CADD

Benign

0.033

(source)

DANN

Benign

0.55

PhyloP100

-2.2

PromoterAI

-0.043

Neutral

(source)

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over