chr12-89351700-C-A

Position:

chr12-89351700-C-A

Variant summary

Our verdict is Benign. Variant got -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

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:

(HGNC:):

links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 id 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/exons	MANE	UniProt
DUSP6	NM_001946.4 linkuse as main transcript	c.340G>T	p.Val114Leu	missense_variant	1/3	ENST00000279488.8
DUSP6	NM_022652.4 linkuse as main transcript	c.340G>T	p.Val114Leu	missense_variant	1/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DUSP6	ENST00000279488.8 linkuse as main transcript	c.340G>T	p.Val114Leu	missense_variant	1/3	1	NM_001946.4	P1	Q16828-1
DUSP6	ENST00000308385.6 linkuse as main transcript	c.340G>T	p.Val114Leu	missense_variant	1/2	1			Q16828-2
	ENST00000611513.1 linkuse as main transcript	n.686C>A		non_coding_transcript_exon_variant	1/1
DUSP6	ENST00000548755.1 linkuse as main transcript	c.340G>T	p.Val114Leu	missense_variant	2/2	4

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

GnomAD3 exomes

AF:

0.523

AC:

117037

AN:

223892

Hom.:

31014

AF XY:

0.521

AC XY:

64258

AN XY:

123448

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 SAS exome

AF:

0.482

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

Gnomad4 AFR exome

AF:

0.289

Gnomad4 AMR exome

AF:

0.512

Gnomad4 ASJ exome

AF:

0.491

Gnomad4 EAS exome

AF:

0.568

Gnomad4 SAS exome

AF:

0.480

Gnomad4 FIN exome

AF:

0.628

Gnomad4 NFE exome

AF:

0.541

Gnomad4 OTH exome

AF:

0.517

GnomAD4 genome

AF:

0.470

AC:

71433

AN:

152080

Hom.:

17862

Cov.:

AF XY:

0.476

AC XY:

35399

AN XY:

74316

show subpopulations

Gnomad4 AFR

AF:

0.292

Gnomad4 AMR

AF:

0.489

Gnomad4 ASJ

AF:

0.501

Gnomad4 EAS

AF:

0.613

Gnomad4 SAS

AF:

0.487

Gnomad4 FIN

AF:

0.630

Gnomad4 NFE

AF:

0.533

Gnomad4 OTH

AF:

0.483

Alfa

AF:

0.515

Hom.:

37904

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

Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 09, 2018	This variant is associated with the following publications: (PMID: 22155192, 27346686) -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Hypogonadotropic hypogonadism 19 with or without anosmia

Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 30, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

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

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;.

MutationTaster

Benign

7.2e-9

P;P

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

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

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