chr12-89351700-C-T

Variant names:

• chr12-89351700-C-T
• rs2279574
• NM_001946.4:c.340G>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_001946.4(DUSP6):​c.340G>A​(p.Val114Met) variant causes a missense change. The variant allele was found at a frequency of 0.00000374 in 1,603,928 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V114L) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: DUSP6 NM_001946.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.05
• Publications: 56 publications found

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 Gene-Disease associations (from GenCC):

• hypogonadotropic hypogonadism

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Kallmann syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• hypogonadotropic hypogonadism 19 with or without anosmia

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)

ENSG00000274021 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001946.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DUSP6	NM_001946.4	MANE Select	c.340G>A	p.Val114Met	missense	Exon 1 of 3	NP_001937.2
	DUSP6	NM_022652.4		c.340G>A	p.Val114Met	missense	Exon 1 of 2	NP_073143.2
	POC1B-DUSP6	NM_001425794.1		c.1114-2139G>A		intron	N/A	NP_001412723.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DUSP6	ENST00000279488.8	TSL:1 MANE Select	c.340G>A	p.Val114Met	missense	Exon 1 of 3	ENSP00000279488.6
	DUSP6	ENST00000308385.6	TSL:1	c.340G>A	p.Val114Met	missense	Exon 1 of 2	ENSP00000307835.6
	DUSP6	ENST00000548755.1	TSL:4	c.340G>A	p.Val114Met	missense	Exon 2 of 2	ENSP00000446858.1

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152006 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000725

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000207 AC: 3 AN: 1451922 Hom.: 0 Cov.: 97 AF XY: 0.00000277 AC XY: 2 AN XY: 721512

African (AFR) AF: 0.0000901 AC: 3 AN: 33292

American (AMR) AF: 0.00 AC: 0 AN: 43908

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25956

East Asian (EAS) AF: 0.00 AC: 0 AN: 39126

South Asian (SAS) AF: 0.00 AC: 0 AN: 84932

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51112

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5748

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1107884

Other (OTH) AF: 0.00 AC: 0 AN: 59964

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152006 Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1 AN XY: 74220

African (AFR) AF: 0.0000725 AC: 3 AN: 41392

American (AMR) AF: 0.00 AC: 0 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10572

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67986

Other (OTH) AF: 0.00 AC: 0 AN: 2086

Alfa AF: 0.00 Hom.: 54718

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.33
BayesDel_addAF	Uncertain	0.056	T
BayesDel_noAF	Benign	-0.16
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.30	T
Eigen	Pathogenic	0.74
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Benign	0.022	T
MetaRNN	Uncertain	0.53	D
MetaSVM	Benign	-0.51	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		6.1
PrimateAI	Pathogenic	0.84	D
PROVEAN	Benign	-1.8	N
REVEL	Benign	0.22
Sift	Benign	0.047	D
Sift4G	Benign	0.11	T
Polyphen		1.0	D
Vest4		0.52
MutPred		0.40		Gain of catalytic residue at S113 (P = 0)
MVP		0.53
MPC		1.3
ClinPred		0.97	D
GERP RS		5.1
Varity_R		0.48
gMVP		0.71
Mutation Taster		=53/47	polymorphism

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

Other links and lift over

dbSNP: rs2279574; hg19: chr12-89745477;