12-89351700-C-G

Variant summary

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

The NM_001946.4(DUSP6):c.340G>C(p.Val114Leu) 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Benignin ClinVar.

• Frequency: Genomes: not found (cov: 33)
• Consequence: DUSP6 NM_001946.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.05

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]

(HGNC:):

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=0.40769577).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DUSP6	NM_001946.4	c.340G>C	p.Val114Leu	missense_variant	1/3	ENST00000279488.8
DUSP6	NM_022652.4	c.340G>C	p.Val114Leu	missense_variant	1/2

Ensembl

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

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 97

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.29
BayesDel_addAF	Benign	-0.070	T
BayesDel_noAF	Benign	-0.34
Cadd	Uncertain	23
Dann	Uncertain	1.0
DEOGEN2	Benign	0.12	T;.;.
Eigen	Uncertain	0.28
Eigen_PC	Uncertain	0.36
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Benign	0.78	T;T;T
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.41	T;T;T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	1.5	L;L;.
MutationTaster	Benign	7.2e-9	P;P
PrimateAI	Pathogenic	0.82	D
PROVEAN	Benign	-1.8	N;N;N
REVEL	Benign	0.082
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);
MVP		0.41
MPC		0.75
ClinPred		0.96	D
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

Other links and lift over

dbSNP: rs2279574; hg19: chr12-89745477;