rs2279574

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001946.4(DUSP6):c.340G>T(p.Val114Leu) variant causes a missense change. The variant allele was found at a frequency of 0.526 in 1,603,502 control chromosomes in the GnomAD database, including 225,598 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.47 ( 17862 hom., cov: 33)

Exomes 𝑓: 0.53 ( 207736 hom. )

Consequence

DUSP6
NM_001946.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 6.05

Publications

56 publications found

Variant links:

Genes affected

DUSP6 (HGNC:3072): (dual specificity phosphatase 6) The protein encoded by this gene is a member of the dual specificity protein phosphatase subfamily. These phosphatases inactivate their target kinases by dephosphorylating both the phosphoserine/threonine and phosphotyrosine residues. They negatively regulate members of the mitogen-activated protein (MAP) kinase superfamily (MAPK/ERK, SAPK/JNK, p38), which are associated with cellular proliferation and differentiation. Different members of the family of dual specificity phosphatases show distinct substrate specificities for various MAP kinases, different tissue distribution and subcellular localization, and different modes of inducibility of their expression by extracellular stimuli. This gene product inactivates ERK2, is expressed in a variety of tissues with the highest levels in heart and pancreas, and unlike most other members of this family, is localized in the cytoplasm. Mutations in this gene have been associated with congenital hypogonadotropic hypogonadism. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Jan 2014]

DUSP6 Gene-Disease associations (from GenCC):

hypogonadotropic hypogonadism
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
Kallmann syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
hypogonadotropic hypogonadism 19 with or without anosmia
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)

DUSP6 links:

ENSG00000274021 (HGNC:):

ENSG00000274021 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

BP4

Computational evidence support a benign effect (MetaRNN=3.374517E-4).

BP6

Variant 12-89351700-C-A is Benign according to our data. Variant chr12-89351700-C-A is described in ClinVar as Benign. ClinVar VariationId is 802882.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.595 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DUSP6	NM_001946.4 link	c.340G>T	p.Val114Leu	missense_variant	Exon 1 of 3	ENST00000279488.8	NP_001937.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DUSP6	ENST00000279488.8 link	c.340G>T	p.Val114Leu	missense_variant	Exon 1 of 3	1	NM_001946.4	ENSP00000279488.6

Frequencies

GnomAD3 genomes

AF:

0.470

AC:

71409

AN:

151962

Hom.:

17860

Cov.:

show subpopulations

Gnomad AFR

AF:

0.292

Gnomad AMI

AF:

0.555

Gnomad AMR

AF:

0.490

Gnomad ASJ

AF:

0.501

Gnomad EAS

AF:

0.613

Gnomad SAS

AF:

0.487

Gnomad FIN

AF:

0.630

Gnomad MID

AF:

0.468

Gnomad NFE

AF:

0.533

Gnomad OTH

AF:

0.477

GnomAD2 exomes

AF:

0.523

AC:

117037

AN:

223892

AF XY:

0.521

show subpopulations

Gnomad AFR exome

AF:

0.277

Gnomad AMR exome

AF:

0.517

Gnomad ASJ exome

AF:

0.487

Gnomad EAS exome

AF:

0.609

Gnomad FIN exome

AF:

0.626

Gnomad NFE exome

AF:

0.537

Gnomad OTH exome

AF:

0.525

GnomAD4 exome

AF:

0.532

AC:

772516

AN:

1451422

Hom.:

207736

Cov.:

AF XY:

0.531

AC XY:

382807

AN XY:

721194

show subpopulations

African (AFR)

AF:

0.289

AC:

9632

AN:

33282

American (AMR)

AF:

0.512

AC:

22454

AN:

43854

Ashkenazi Jewish (ASJ)

AF:

0.491

AC:

12745

AN:

25944

East Asian (EAS)

AF:

0.568

AC:

22188

AN:

39096

South Asian (SAS)

AF:

0.480

AC:

40761

AN:

84896

European-Finnish (FIN)

AF:

0.628

AC:

32061

AN:

51086

Middle Eastern (MID)

AF:

0.495

AC:

2843

AN:

5748

European-Non Finnish (NFE)

AF:

0.541

AC:

598852

AN:

1107580

Other (OTH)

AF:

0.517

AC:

30980

AN:

59936

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

26609

53217

79826

106434

133043

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

16948

33896

50844

67792

84740

<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:

0.470

AC:

71433

AN:

152080

Hom.:

17862

Cov.:

AF XY:

0.476

AC XY:

35399

AN XY:

74316

show subpopulations

African (AFR)

AF:

0.292

AC:

12123

AN:

41502

American (AMR)

AF:

0.489

AC:

7481

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.501

AC:

1739

AN:

3468

East Asian (EAS)

AF:

0.613

AC:

3156

AN:

5152

South Asian (SAS)

AF:

0.487

AC:

2352

AN:

4826

European-Finnish (FIN)

AF:

0.630

AC:

6663

AN:

10568

Middle Eastern (MID)

AF:

0.480

AC:

141

AN:

294

European-Non Finnish (NFE)

AF:

0.533

AC:

36257

AN:

67970

Other (OTH)

AF:

0.483

AC:

1017

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1904

3809

5713

7618

9522

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

660

1320

1980

2640

3300

<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:

0.504

Hom.:

54718

Bravo

AF:

0.454

TwinsUK

AF:

0.557

AC:

2065

ALSPAC

AF:

0.561

AC:

2162

ESP6500AA

AF:

0.282

AC:

1219

ESP6500EA

AF:

0.508

AC:

4297

ExAC

AF:

0.502

AC:

59948

Asia WGS

AF:

0.559

AC:

1943

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Aug 09, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 22155192, 27346686) -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Hypogonadotropic hypogonadism 19 with or without anosmia

Benign:2

May 28, 2019

Mendelics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 30, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.29

BayesDel_addAF

Benign

-0.49

BayesDel_noAF

Benign

-0.34

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.12

T;.;.

Eigen

Uncertain

0.28

Eigen_PC

Uncertain

0.36

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.78

T;T;T

MetaRNN

Benign

0.00034

T;T;T

MetaSVM

Benign

-0.91

MutationAssessor

Benign

1.5

L;L;.

PhyloP100

6.1

PrimateAI

Pathogenic

0.82

PROVEAN

Benign

-1.8

N;N;N

REVEL

Benign

0.099

Sift

Uncertain

0.014

D;T;T

Sift4G

Benign

0.27

T;T;T

Polyphen

0.78

P;B;.

Vest4

0.13

MutPred

0.27

Gain of catalytic residue at L115 (P = 2e-04);Gain of catalytic residue at L115 (P = 2e-04);Gain of catalytic residue at L115 (P = 2e-04);

MPC

0.75

ClinPred

0.026

GERP RS

5.1

Varity_R

0.57

gMVP

0.73

Mutation Taster

=72/28

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over