rs143946794
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
NM_001946.4 missense
Scores
1
18
Clinical Significance
Conservation
PhyloP100: 2.27
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]
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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 GnomAd at 29 AD,Digenic gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
DUSP6 | NM_001946.4 | c.566A>G | p.Asn189Ser | missense_variant | 2/3 | ENST00000279488.8 | |
DUSP6 | NM_022652.4 | c.400+780A>G | intron_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
DUSP6 | ENST00000279488.8 | c.566A>G | p.Asn189Ser | missense_variant | 2/3 | 1 | NM_001946.4 | P1 | |
DUSP6 | ENST00000308385.6 | c.400+780A>G | intron_variant | 1 | |||||
DUSP6 | ENST00000547291.1 | c.191A>G | p.Asn64Ser | missense_variant | 1/2 | 2 | |||
DUSP6 | ENST00000547140.1 | n.252A>G | non_coding_transcript_exon_variant | 2/3 | 3 |
Frequencies
GnomAD3 genomes ? AF: 0.000191 AC: 29AN: 152106Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000195 AC: 49AN: 251356Hom.: 0 AF XY: 0.000213 AC XY: 29AN XY: 135862
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GnomAD4 exome AF: 0.000242 AC: 354AN: 1461826Hom.: 1 Cov.: 30 AF XY: 0.000256 AC XY: 186AN XY: 727210
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GnomAD4 genome ? AF: 0.000191 AC: 29AN: 152224Hom.: 0 Cov.: 32 AF XY: 0.000188 AC XY: 14AN XY: 74432
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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 | Invitae | 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:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
Cadd
Benign
Dann
Benign
DEOGEN2
Benign
T;T
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Benign
D
LIST_S2
Uncertain
D;D
M_CAP
Benign
T
MetaRNN
Benign
T;T
MetaSVM
Benign
T
MutationAssessor
Benign
N;.
MutationTaster
Benign
D;D;D
PrimateAI
Benign
T
PROVEAN
Benign
N;N
REVEL
Benign
Sift
Benign
T;T
Sift4G
Benign
T;T
Polyphen
B;.
Vest4
MVP
MPC
ClinPred
T
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at