chr12-89350617-T-C

Variant names:

• chr12-89350617-T-C
• rs867055342
• NM_001946.4:c.809A>G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001946.4(DUSP6):​c.809A>G​(p.Gln270Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,550 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: DUSP6 NM_001946.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.99

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DUSP6	NM_001946.4	c.809A>G	p.Gln270Arg	missense_variant	Exon 2 of 3	ENST00000279488.8	NP_001937.2
DUSP6	NM_022652.4	c.400+1023A>G		intron_variant	Intron 1 of 1		NP_073143.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DUSP6	ENST00000279488.8	c.809A>G	p.Gln270Arg	missense_variant	Exon 2 of 3	1	NM_001946.4	ENSP00000279488.6
DUSP6	ENST00000308385.6	c.400+1023A>G		intron_variant	Intron 1 of 1	1		ENSP00000307835.6
DUSP6	ENST00000547291.1	c.434A>G	p.Gln145Arg	missense_variant	Exon 1 of 2	2		ENSP00000449838.1
DUSP6	ENST00000547140.1	n.495A>G		non_coding_transcript_exon_variant	Exon 2 of 3	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251436 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135890

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461550 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 727016

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000447

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.0000151

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

May 18, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.809A>G (p.Q270R) alteration is located in exon 2 (coding exon 2) of the DUSP6 gene. This alteration results from a A to G substitution at nucleotide position 809, causing the glutamine (Q) at amino acid position 270 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.54
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.12
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.49	T;T
Eigen	Benign	0.18
Eigen_PC	Uncertain	0.36
FATHMM_MKL	Benign	0.41	N
LIST_S2	Benign	0.66	T;T
M_CAP	Benign	0.053	D
MetaRNN	Uncertain	0.68	D;D
MetaSVM	Uncertain	-0.22	T
MutationAssessor	Benign	1.1	L;.
PrimateAI	Uncertain	0.78	T
PROVEAN	Benign	-2.3	N;N
REVEL	Uncertain	0.49
Sift	Benign	0.060	T;T
Sift4G	Benign	0.18	T;T
Polyphen		0.10	B;.
Vest4		0.84
MutPred		0.42		Gain of catalytic residue at Q266 (P = 0.0029);.;
MVP		0.97
MPC		0.90
ClinPred		0.48	T
GERP RS		5.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.66
gMVP		0.78

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: rs867055342; hg19: chr12-89744394;