rs2279574

chr12-89351700-C-Achr12-89351700-C-Gchr12-89351700-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001946.4(DUSP6):c.340G>T(p.Val114Leu) variant causes a missense change. The variant allele was found at a frequency of 0.526 in 1,603,502 control chromosomes in the GnomAD database, including 225,598 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.47 (17862 hom., cov: 33)
  • Exomes 𝑓: 0.53 (207736 hom.)
• Consequence: DUSP6 NM_001946.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• 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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=3.374517E-4).
• BP6: Variant 12-89351700-C-A is Benign according to our data. Variant chr12-89351700-C-A is described in ClinVar as [Benign]. Clinvar id is 802882.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.595 is higher than 0.05.

Transcripts

RefSeq

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

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.470 AC: 71409 AN: 151962 Hom.: 17860 Cov.: 33

Gnomad AFR AF: 0.292

Gnomad AMI AF: 0.555

Gnomad AMR AF: 0.490

Gnomad ASJ AF: 0.501

Gnomad EAS AF: 0.613

Gnomad SAS AF: 0.487

Gnomad FIN AF: 0.630

Gnomad MID AF: 0.468

Gnomad NFE AF: 0.533

Gnomad OTH AF: 0.477

GnomAD3 exomes AF: 0.523 AC: 117037 AN: 223892 Hom.: 31014 AF XY: 0.521 AC XY: 64258 AN XY: 123448

Gnomad AFR exome AF: 0.277

Gnomad AMR exome AF: 0.517

Gnomad ASJ exome AF: 0.487

Gnomad EAS exome AF: 0.609

Gnomad SAS exome AF: 0.482

Gnomad FIN exome AF: 0.626

Gnomad NFE exome AF: 0.537

Gnomad OTH exome AF: 0.525

GnomAD4 exome AF: 0.532 AC: 772516 AN: 1451422 Hom.: 207736 Cov.: 97 AF XY: 0.531 AC XY: 382807 AN XY: 721194

Gnomad4 AFR exome AF: 0.289

Gnomad4 AMR exome AF: 0.512

Gnomad4 ASJ exome AF: 0.491

Gnomad4 EAS exome AF: 0.568

Gnomad4 SAS exome AF: 0.480

Gnomad4 FIN exome AF: 0.628

Gnomad4 NFE exome AF: 0.541

Gnomad4 OTH exome AF: 0.517

GnomAD4 genome AF: 0.470 AC: 71433 AN: 152080 Hom.: 17862 Cov.: 33 AF XY: 0.476 AC XY: 35399 AN XY: 74316

Gnomad4 AFR AF: 0.292

Gnomad4 AMR AF: 0.489

Gnomad4 ASJ AF: 0.501

Gnomad4 EAS AF: 0.613

Gnomad4 SAS AF: 0.487

Gnomad4 FIN AF: 0.630

Gnomad4 NFE AF: 0.533

Gnomad4 OTH AF: 0.483

Alfa AF: 0.515 Hom.: 37904

Bravo AF: 0.454

TwinsUK AF: 0.557 AC: 2065

ALSPAC AF: 0.561 AC: 2162

ESP6500AA AF: 0.282 AC: 1219

ESP6500EA AF: 0.508 AC: 4297

ExAC AF: 0.502 AC: 59948

Asia WGS AF: 0.559 AC: 1943 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hypogonadotropic hypogonadism 19 with or without anosmia Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 30, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 09, 2018	This variant is associated with the following publications: (PMID: 22155192, 27346686) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.29
BayesDel_addAF	Benign	-0.49	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	Pathogenic	0.98	D
LIST_S2	Benign	0.78	T;T;T
MetaRNN	Benign	0.00034	T;T;T
MetaSVM	Benign	-0.91	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	0.099
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);
MPC		0.75
ClinPred		0.026	T
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; COSMIC: COSV54378597; COSMIC: COSV54378597;