rs704076

Variant names:

• chr12-89350144-C-A
• rs704076
• NM_001946.4:c.838+444G>T

Your query was ambiguous. Multiple possible variants found:

• chr12-89350144-C-A
• chr12-89350144-C-T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001946.4(DUSP6):​c.838+444G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.243 in 152,162 control chromosomes in the GnomAD database, including 5,186 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.24 (5186 hom., cov: 33)
• Consequence: DUSP6 NM_001946.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.154
• Publications: 8 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.74).
• 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.838+444G>T		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.838+444G>T		intron_variant	Intron 2 of 2	1	NM_001946.4	ENSP00000279488.6
DUSP6	ENST00000308385.6	c.401-583G>T		intron_variant	Intron 1 of 1	1		ENSP00000307835.6
DUSP6	ENST00000547291.1	c.463+444G>T		intron_variant	Intron 1 of 1	2		ENSP00000449838.1
DUSP6	ENST00000547140.1	n.524+444G>T		intron_variant	Intron 2 of 2	3

Frequencies

GnomAD3 genomes AF: 0.242 AC: 36854 AN: 152044 Hom.: 5177 Cov.: 33

Gnomad AFR AF: 0.385

Gnomad AMI AF: 0.291

Gnomad AMR AF: 0.240

Gnomad ASJ AF: 0.173

Gnomad EAS AF: 0.0291

Gnomad SAS AF: 0.167

Gnomad FIN AF: 0.157

Gnomad MID AF: 0.180

Gnomad NFE AF: 0.195

Gnomad OTH AF: 0.226

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

GnomAD4 genome AF: 0.243 AC: 36904 AN: 152162 Hom.: 5186 Cov.: 33 AF XY: 0.238 AC XY: 17669 AN XY: 74394

African (AFR) AF: 0.385 AC: 15989 AN: 41480

American (AMR) AF: 0.240 AC: 3663 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.173 AC: 601 AN: 3472

East Asian (EAS) AF: 0.0293 AC: 152 AN: 5182

South Asian (SAS) AF: 0.167 AC: 806 AN: 4826

European-Finnish (FIN) AF: 0.157 AC: 1660 AN: 10592

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

European-Non Finnish (NFE) AF: 0.195 AC: 13244 AN: 68010

Other (OTH) AF: 0.224 AC: 473 AN: 2112

Alfa AF: 0.152 Hom.: 381

Bravo AF: 0.255

Asia WGS AF: 0.123 AC: 431 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
CADD	Benign	9.6
DANN	Benign	0.78
PhyloP100		-0.15
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
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: rs704076; hg19: chr12-89743921;