12-89351049-A-G

Variant names:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001946.4(DUSP6):c.401-24T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.114 in 1,550,784 control chromosomes in the GnomAD database, including 10,712 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). There are indicators that this mutation may affect the branch point..

Frequency

Genomes: 𝑓 0.12 ( 1243 hom., cov: 32)

Exomes 𝑓: 0.11 ( 9469 hom. )

Consequence

DUSP6
NM_001946.4 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -0.148

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 links:

ENSG00000274021 (HGNC:):

ENSG00000274021 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

This position, referring to a specific DNA site, is a probable branch point but is likely benign (scored 2 / 10, using the threshold of <=3). The score ranges from 0 to 10, with values ≤3 considered benign and >5 classified as pathogenic. Computational evidence support a benign effect (MetaRNN=0.0020593107).

BP6

Variant 12-89351049-A-G is Benign according to our data. Variant chr12-89351049-A-G is described in ClinVar as [Benign]. Clinvar id is 1292720.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.167 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DUSP6	NM_001946.4 link	c.401-24T>C		intron_variant	Intron 1 of 2	ENST00000279488.8	NP_001937.2	Q16828-1A0A024RBC1
DUSP6	NM_022652.4 link	c.400+591T>C		intron_variant	Intron 1 of 1		NP_073143.2	Q16828-2Q53GP9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DUSP6	ENST00000279488.8 link	c.401-24T>C		intron_variant	Intron 1 of 2	1	NM_001946.4	ENSP00000279488.6		Q16828-1

Frequencies

GnomAD3 genomes

AF:

0.125

AC:

18994

AN:

152086

Hom.:

1241

Cov.:

show subpopulations

Gnomad AFR

AF:

0.140

Gnomad AMI

AF:

0.250

Gnomad AMR

AF:

0.173

Gnomad ASJ

AF:

0.103

Gnomad EAS

AF:

0.0229

Gnomad SAS

AF:

0.0908

Gnomad FIN

AF:

0.121

Gnomad MID

AF:

0.114

Gnomad NFE

AF:

0.115

Gnomad OTH

AF:

0.124

GnomAD3 exomes

AF:

0.118

AC:

18738

AN:

159412

Hom.:

1272

AF XY:

0.114

AC XY:

9832

AN XY:

86480

show subpopulations

Gnomad AFR exome

AF:

0.145

Gnomad AMR exome

AF:

0.189

Gnomad ASJ exome

AF:

0.105

Gnomad EAS exome

AF:

0.0235

Gnomad SAS exome

AF:

0.0974

Gnomad FIN exome

AF:

0.114

Gnomad NFE exome

AF:

0.113

Gnomad OTH exome

AF:

0.125

GnomAD4 exome

AF:

0.113

AC:

158297

AN:

1398580

Hom.:

9469

Cov.:

AF XY:

0.112

AC XY:

77413

AN XY:

691374

show subpopulations

Gnomad4 AFR exome

AF:

0.137

Gnomad4 AMR exome

AF:

0.186

Gnomad4 ASJ exome

AF:

0.108

Gnomad4 EAS exome

AF:

0.0237

Gnomad4 SAS exome

AF:

0.0965

Gnomad4 FIN exome

AF:

0.108

Gnomad4 NFE exome

AF:

0.115

Gnomad4 OTH exome

AF:

0.114

GnomAD4 genome

AF:

0.125

AC:

19014

AN:

152204

Hom.:

1243

Cov.:

AF XY:

0.125

AC XY:

9283

AN XY:

74420

show subpopulations

Gnomad4 AFR

AF:

0.140

Gnomad4 AMR

AF:

0.173

Gnomad4 ASJ

AF:

0.103

Gnomad4 EAS

AF:

0.0230

Gnomad4 SAS

AF:

0.0913

Gnomad4 FIN

AF:

0.121

Gnomad4 NFE

AF:

0.115

Gnomad4 OTH

AF:

0.124

Alfa

AF:

0.109

Hom.:

854

Bravo

AF:

0.131

TwinsUK

AF:

0.107

AC:

397

ALSPAC

AF:

0.108

AC:

415

ESP6500AA

AF:

0.126

AC:

551

ESP6500EA

AF:

0.111

AC:

950

ExAC

AF:

0.0786

AC:

9002

Asia WGS

AF:

0.0690

AC:

239

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Aug 09, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.82

BayesDel_noAF

Benign

-0.81

CADD

Benign

DANN

Benign

0.51

DEOGEN2

Benign

0.0071

Eigen

Benign

-1.0

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.050

LIST_S2

Uncertain

0.90

MetaRNN

Benign

0.0021

MetaSVM

Benign

-0.91

PROVEAN

Benign

0.48

REVEL

Benign

0.093

Sift

Uncertain

0.017

Sift4G

Uncertain

0.018

Vest4

0.019

ClinPred

0.0026

GERP RS

-3.0

BranchPoint Hunter

2.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over