rs769700

Variant names:

• chr12-89349837-A-G
• rs769700
• NM_001946.4:c.839-276T>C

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001946.4(DUSP6):​c.839-276T>C 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 152,178 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: 1.28
• Publications: 6 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: Ambry Genetics, Labcorp Genetics (formerly Invitae)

POC1B-DUSP6 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.53).
• BP6: Variant 12-89349837-A-G is Benign according to our data. Variant chr12-89349837-A-G is described in ClinVar as Benign. ClinVar VariationId is 1237614.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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DUSP6	NM_001946.4	c.839-276T>C		intron_variant	Intron 2 of 2	ENST00000279488.8	NP_001937.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DUSP6	ENST00000279488.8	c.839-276T>C		intron_variant	Intron 2 of 2	1	NM_001946.4	ENSP00000279488.6
DUSP6	ENST00000308385.6	c.401-276T>C		intron_variant	Intron 1 of 1	1		ENSP00000307835.6
DUSP6	ENST00000547291.1	c.464-276T>C		intron_variant	Intron 1 of 1	2		ENSP00000449838.1
DUSP6	ENST00000547140.1	n.525-276T>C		intron_variant	Intron 2 of 2	3

Frequencies

GnomAD3 genomes AF: 0.242 AC: 36824 AN: 152060 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: 0.166

Gnomad FIN AF: 0.157

Gnomad MID AF: 0.180

Gnomad NFE AF: 0.195

Gnomad OTH AF: 0.224

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

GnomAD4 genome AF: 0.242 AC: 36874 AN: 152178 Hom.: 5171 Cov.: 33 AF XY: 0.237 AC XY: 17660 AN XY: 74412

African (AFR) AF: 0.385 AC: 15976 AN: 41482

American (AMR) AF: 0.239 AC: 3661 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.173 AC: 600 AN: 3468

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

South Asian (SAS) AF: 0.166 AC: 803 AN: 4828

European-Finnish (FIN) AF: 0.157 AC: 1660 AN: 10598

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

European-Non Finnish (NFE) AF: 0.195 AC: 13236 AN: 68004

Other (OTH) AF: 0.223 AC: 470 AN: 2112

Alfa AF: 0.207 Hom.: 5446

Bravo AF: 0.255

Asia WGS AF: 0.124 AC: 432 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Aug 09, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.53
CADD	Benign	18
DANN	Benign	0.81
PhyloP100		1.3
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: rs769700; hg19: chr12-89743614;