2-96144879-C-T

Variant names:

• chr2-96144879-C-T
• rs779039146
• NM_004418.4:c.392G>A

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_004418.4(DUSP2):​c.392G>A​(p.Gly131Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000129 in 1,548,628 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 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. G131V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
• Consequence: DUSP2 NM_004418.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.33
• Publications: 4 publications found

Genes affected

DUSP2 (HGNC:3068): (dual specificity phosphatase 2) 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 ERK1 and ERK2, is predominantly expressed in hematopoietic tissues, and is localized in the nucleus. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.979

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004418.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DUSP2	NM_004418.4	MANE Select	c.392G>A	p.Gly131Asp	missense	Exon 2 of 4	NP_004409.1	Q05923

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DUSP2	ENST00000288943.5	TSL:1 MANE Select	c.392G>A	p.Gly131Asp	missense	Exon 2 of 4	ENSP00000288943.4	Q05923
	DUSP2	ENST00000718436.1		c.392G>A	p.Gly131Asp	missense	Exon 2 of 4	ENSP00000520821.1	Q05923
	DUSP2	ENST00000914868.1		c.389G>A	p.Gly130Asp	missense splice_region	Exon 2 of 4	ENSP00000584927.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152170 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

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

GnomAD2 exomes AF: 0.00000671 AC: 1 AN: 149114 AF XY: 0.0000126

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000181

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 7.16e-7 AC: 1 AN: 1396344 Hom.: 0 Cov.: 31 AF XY: 0.00000145 AC XY: 1 AN XY: 688250

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 31800

American (AMR) AF: 0.00 AC: 0 AN: 35278

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24956

East Asian (EAS) AF: 0.00 AC: 0 AN: 36128

South Asian (SAS) AF: 0.00 AC: 0 AN: 79020

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48144

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5672

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1077490

Other (OTH) AF: 0.0000173 AC: 1 AN: 57856

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152284 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74464

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000241 AC: 1 AN: 41572

American (AMR) AF: 0.00 AC: 0 AN: 15310

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5162

South Asian (SAS) AF: 0.00 AC: 0 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68012

Other (OTH) AF: 0.00 AC: 0 AN: 2116

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.0000868 Hom.: 0

ExAC AF: 0.00000932 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.93
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.030
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.59	D
Eigen	Uncertain	0.62
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.80	T
M_CAP	Pathogenic	0.64	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Uncertain	0.51	D
MutationAssessor	Pathogenic	3.2	M
PhyloP100		3.3
PrimateAI	Pathogenic	0.89	D
PROVEAN	Pathogenic	-5.9	D
REVEL	Pathogenic	0.77
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.013	D
Polyphen		1.0	D
Vest4		0.63
MutPred		0.92		Loss of methylation at R129 (P = 0.1674)
MVP		0.80
MPC		0.46
ClinPred		0.99	D
GERP RS		4.4
Varity_R		0.86
gMVP		0.85
Mutation Taster		=55/45	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs779039146; hg19: chr2-96810618; COSMIC: COSV56620526; COSMIC: COSV56620526;