rs769701

Variant names:

• chr12-89349812-G-A
• rs769701
• NM_001946.4:c.839-251C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Moderate BP6_Moderate BA1

The NM_001946.4(DUSP6):​c.839-251C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.242 in 152,120 control chromosomes in the GnomAD database, including 5,171 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.24 (5171 hom., cov: 33)
• Consequence: DUSP6 NM_001946.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.79
• Publications: 4 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.41).
• BP6: Variant 12-89349812-G-A is Benign according to our data. Variant chr12-89349812-G-A is described in ClinVar as Benign. ClinVar VariationId is 1226329.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.38 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.839-251C>T		intron	N/A	NP_001937.2
	POC1B-DUSP6	NM_001425794.1		c.1114-251C>T		intron	N/A	NP_001412723.1
	POC1B-DUSP6	NM_001425795.1		c.1033-251C>T		intron	N/A	NP_001412724.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DUSP6	ENST00000279488.8	TSL:1 MANE Select	c.839-251C>T		intron	N/A	ENSP00000279488.6	Q16828-1
	DUSP6	ENST00000308385.6	TSL:1	c.401-251C>T		intron	N/A	ENSP00000307835.6	Q16828-2
	DUSP6	ENST00000924807.1		c.497-251C>T		intron	N/A	ENSP00000594866.1

Frequencies

GnomAD3 genomes AF: 0.242 AC: 36821 AN: 152002 Hom.: 5162 Cov.: 33

Gnomad AFR AF: 0.385

Gnomad AMI AF: 0.291

Gnomad AMR AF: 0.239

Gnomad ASJ AF: 0.173

Gnomad EAS AF: 0.0290

Gnomad SAS AF: 0.167

Gnomad FIN AF: 0.157

Gnomad MID AF: 0.180

Gnomad NFE AF: 0.195

Gnomad OTH AF: 0.225

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.242 AC: 36871 AN: 152120 Hom.: 5171 Cov.: 33 AF XY: 0.237 AC XY: 17655 AN XY: 74374

African (AFR) AF: 0.385 AC: 15968 AN: 41452

American (AMR) AF: 0.239 AC: 3662 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.173 AC: 601 AN: 3470

East Asian (EAS) AF: 0.0293 AC: 152 AN: 5188

South Asian (SAS) AF: 0.166 AC: 804 AN: 4830

European-Finnish (FIN) AF: 0.157 AC: 1660 AN: 10580

Middle Eastern (MID) AF: 0.173 AC: 51 AN: 294

European-Non Finnish (NFE) AF: 0.195 AC: 13236 AN: 67990

Other (OTH) AF: 0.223 AC: 472 AN: 2112

Alfa AF: 0.240 Hom.: 618

Bravo AF: 0.255

Asia WGS AF: 0.124 AC: 432 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.41
CADD	Benign	17
DANN	Benign	0.85
PhyloP100		1.8
Mutation Taster		=100/0	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: rs769701; hg19: chr12-89743589;