chr12-89350860-T-C

Position:

chr12-89350860-T-C

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_001946.4(DUSP6):c.566A>G(p.Asn189Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000237 in 1,614,050 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00019 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00024 ( 1 hom. )

Consequence

DUSP6
NM_001946.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter P:1U:1

Conservation

PhyloP100: 2.27

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.039555818).

BS2

High AC in GnomAd4 at 29 AD,Digenic gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DUSP6	NM_001946.4 linkuse as main transcript	c.566A>G	p.Asn189Ser	missense_variant	2/3	ENST00000279488.8	NP_001937.2
DUSP6	NM_022652.4 linkuse as main transcript	c.400+780A>G		intron_variant			NP_073143.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DUSP6	ENST00000279488.8 linkuse as main transcript	c.566A>G	p.Asn189Ser	missense_variant	2/3	1	NM_001946.4	ENSP00000279488	P1	Q16828-1
DUSP6	ENST00000308385.6 linkuse as main transcript	c.400+780A>G		intron_variant		1		ENSP00000307835		Q16828-2
DUSP6	ENST00000547291.1 linkuse as main transcript	c.191A>G	p.Asn64Ser	missense_variant	1/2	2		ENSP00000449838
DUSP6	ENST00000547140.1 linkuse as main transcript	n.252A>G		non_coding_transcript_exon_variant	2/3	3

Frequencies

GnomAD3 genomes

AF:

0.000191

AC:

AN:

152106

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000382

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000195

AC:

AN:

251356

Hom.:

AF XY:

0.000213

AC XY:

AN XY:

135862

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000578

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000653

Gnomad FIN exome

AF:

0.000231

Gnomad NFE exome

AF:

0.000352

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000242

AC:

354

AN:

1461826

Hom.:

Cov.:

AF XY:

0.000256

AC XY:

186

AN XY:

727210

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.000112

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000348

Gnomad4 FIN exome

AF:

0.000131

Gnomad4 NFE exome

AF:

0.000297

Gnomad4 OTH exome

AF:

0.000132

GnomAD4 genome

AF:

0.000191

AC:

AN:

152224

Hom.:

Cov.:

AF XY:

0.000188

AC XY:

AN XY:

74432

show subpopulations

Gnomad4 AFR

AF:

0.0000481

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000208

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000382

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000340

Hom.:

Bravo

AF:

0.000170

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000465

AC:

ExAC

AF:

0.000181

AC:

EpiCase

AF:

0.000327

EpiControl

AF:

0.000296

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Hypogonadotropic hypogonadism 19 with or without anosmia

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

May 02, 2013

- -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

May 06, 2022

This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 189 of the DUSP6 protein (p.Asn189Ser). This variant is present in population databases (rs143946794, gnomAD 0.04%). This missense change has been observed in individual(s) with Kallman syndrome (PMID: 23643382). ClinVar contains an entry for this variant (Variation ID: 50854). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The serine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.053

BayesDel_addAF

Benign

-0.59

BayesDel_noAF

Benign

-0.75

CADD

Benign

DANN

Benign

0.62

DEOGEN2

Benign

0.066

T;T

Eigen

Benign

-0.84

Eigen_PC

Benign

-0.62

FATHMM_MKL

Benign

0.55

LIST_S2

Uncertain

0.90

D;D

M_CAP

Benign

0.0052

MetaRNN

Benign

0.040

T;T

MetaSVM

Benign

-0.90

MutationAssessor

Benign

-1.2

N;.

MutationTaster

Benign

0.98

D;D;D

PrimateAI

Benign

0.48

PROVEAN

Benign

0.43

N;N

REVEL

Benign

0.14

Sift

Benign

1.0

T;T

Sift4G

Benign

0.93

T;T

Polyphen

0.0

B;.

Vest4

0.10

MVP

0.42

MPC

0.56

ClinPred

0.019

GERP RS

2.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.065

gMVP

0.34

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