chr12-89351700-C-A

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -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:5
• 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: Labcorp Genetics (formerly Invitae), Ambry Genetics

POC1B-DUSP6 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DUSP6	NM_001946.4	MANE Select	c.340G>T	p.Val114Leu	missense	Exon 1 of 3	NP_001937.2
	DUSP6	NM_022652.4		c.340G>T	p.Val114Leu	missense	Exon 1 of 2	NP_073143.2
	POC1B-DUSP6	NM_001425794.1		c.1114-2139G>T		intron	N/A	NP_001412723.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DUSP6	ENST00000279488.8	TSL:1 MANE Select	c.340G>T	p.Val114Leu	missense	Exon 1 of 3	ENSP00000279488.6	Q16828-1
	DUSP6	ENST00000308385.6	TSL:1	c.340G>T	p.Val114Leu	missense	Exon 1 of 2	ENSP00000307835.6	Q16828-2
	DUSP6	ENST00000924807.1		c.340G>T	p.Val114Leu	missense	Exon 1 of 3	ENSP00000594866.1

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

GnomAD2 exomes AF: 0.523 AC: 117037 AN: 223892 AF XY: 0.521

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 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

African (AFR) AF: 0.289 AC: 9632 AN: 33282

American (AMR) AF: 0.512 AC: 22454 AN: 43854

Ashkenazi Jewish (ASJ) AF: 0.491 AC: 12745 AN: 25944

East Asian (EAS) AF: 0.568 AC: 22188 AN: 39096

South Asian (SAS) AF: 0.480 AC: 40761 AN: 84896

European-Finnish (FIN) AF: 0.628 AC: 32061 AN: 51086

Middle Eastern (MID) AF: 0.495 AC: 2843 AN: 5748

European-Non Finnish (NFE) AF: 0.541 AC: 598852 AN: 1107580

Other (OTH) AF: 0.517 AC: 30980 AN: 59936

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

African (AFR) AF: 0.292 AC: 12123 AN: 41502

American (AMR) AF: 0.489 AC: 7481 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.501 AC: 1739 AN: 3468

East Asian (EAS) AF: 0.613 AC: 3156 AN: 5152

South Asian (SAS) AF: 0.487 AC: 2352 AN: 4826

European-Finnish (FIN) AF: 0.630 AC: 6663 AN: 10568

Middle Eastern (MID) AF: 0.480 AC: 141 AN: 294

European-Non Finnish (NFE) AF: 0.533 AC: 36257 AN: 67970

Other (OTH) AF: 0.483 AC: 1017 AN: 2106

Alfa AF: 0.504 Hom.: 54718

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

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	Hypogonadotropic hypogonadism 19 with or without anosmia (2)

Computational scores

Source: dbNSFP v4.9

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
MetaRNN	Benign	0.00034	T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	1.5	L
PhyloP100		6.1
PrimateAI	Pathogenic	0.82	D
PROVEAN	Benign	-1.8	N
REVEL	Benign	0.099
Sift	Uncertain	0.014	D
Sift4G	Benign	0.27	T
Polyphen		0.78	P
Vest4		0.13
MutPred		0.27		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
Mutation Taster		=72/28	polymorphism (auto)

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; COSMIC: COSV54378597; COSMIC: COSV54378597;