chr12-89349425-C-T

Variant names:

• chr12-89349425-C-T
• NM_001946.4:c.975G>A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001946.4(DUSP6):​c.975G>A​(p.Met325Ile) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: DUSP6 NM_001946.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.85

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.38358876).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DUSP6	NM_001946.4	c.975G>A	p.Met325Ile	missense_variant	Exon 3 of 3	ENST00000279488.8	NP_001937.2
DUSP6	NM_022652.4	c.537G>A	p.Met179Ile	missense_variant	Exon 2 of 2		NP_073143.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DUSP6	ENST00000279488.8	c.975G>A	p.Met325Ile	missense_variant	Exon 3 of 3	1	NM_001946.4	ENSP00000279488.6
DUSP6	ENST00000308385.6	c.537G>A	p.Met179Ile	missense_variant	Exon 2 of 2	1		ENSP00000307835.6
DUSP6	ENST00000547291.1	c.600G>A	p.Met200Ile	missense_variant	Exon 2 of 2	2		ENSP00000449838.1
DUSP6	ENST00000547140.1	n.*57G>A		downstream_gene_variant		3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Oct 22, 2019

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.60
BayesDel_addAF	Uncertain	0.081	D
BayesDel_noAF	Benign	-0.12
CADD	Uncertain	26
DANN	Uncertain	0.98
DEOGEN2	Benign	0.39	T;.;T
Eigen	Benign	-0.015
Eigen_PC	Uncertain	0.24
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.90	D;D;D
M_CAP	Benign	0.036	D
MetaRNN	Benign	0.38	T;T;T
MetaSVM	Benign	-0.50	T
MutationAssessor	Benign	0.0	N;.;.
PrimateAI	Pathogenic	0.89	D
PROVEAN	Benign	-1.8	N;N;N
REVEL	Uncertain	0.32
Sift	Uncertain	0.027	D;D;D
Sift4G	Benign	0.067	T;T;T
Polyphen		0.0060	B;B;.
Vest4		0.48
MutPred		0.47		Gain of methylation at K324 (P = 0.0382);.;.;
MVP		0.80
MPC		0.79
ClinPred		0.74	D
GERP RS		6.0
Varity_R		0.69
gMVP		0.55

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr12-89743202;