12-89350469-T-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001946.4(DUSP6):c.838+119A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.115 in 1,029,348 control chromosomes in the GnomAD database, including 7,218 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.13 (1246 hom., cov: 32)
  • Exomes 𝑓: 0.11 (5972 hom.)
• Consequence: DUSP6 NM_001946.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.00400

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]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 12-89350469-T-G is Benign according to our data. Variant chr12-89350469-T-G is described in ClinVar as [Benign]. Clinvar id is 1225295.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.167 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DUSP6	NM_001946.4	c.838+119A>C		intron_variant		ENST00000279488.8
DUSP6	NM_022652.4	c.401-908A>C		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DUSP6	ENST00000279488.8	c.838+119A>C		intron_variant		1	NM_001946.4	P1
DUSP6	ENST00000308385.6	c.401-908A>C		intron_variant		1
DUSP6	ENST00000547291.1	c.463+119A>C		intron_variant		2
DUSP6	ENST00000547140.1	n.524+119A>C		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.125 AC: 19004 AN: 152016 Hom.: 1244 Cov.: 32

Gnomad AFR AF: 0.141

Gnomad AMI AF: 0.250

Gnomad AMR AF: 0.173

Gnomad ASJ AF: 0.103

Gnomad EAS AF: 0.0231

Gnomad SAS AF: 0.0912

Gnomad FIN AF: 0.120

Gnomad MID AF: 0.117

Gnomad NFE AF: 0.115

Gnomad OTH AF: 0.124

GnomAD4 exome AF: 0.113 AC: 99136 AN: 877214 Hom.: 5972 AF XY: 0.112 AC XY: 49789 AN XY: 446132

Gnomad4 AFR exome AF: 0.136

Gnomad4 AMR exome AF: 0.191

Gnomad4 ASJ exome AF: 0.109

Gnomad4 EAS exome AF: 0.0237

Gnomad4 SAS exome AF: 0.0975

Gnomad4 FIN exome AF: 0.108

Gnomad4 NFE exome AF: 0.116

Gnomad4 OTH exome AF: 0.115

GnomAD4 genome AF: 0.125 AC: 19024 AN: 152134 Hom.: 1246 Cov.: 32 AF XY: 0.125 AC XY: 9287 AN XY: 74372

Gnomad4 AFR AF: 0.140

Gnomad4 AMR AF: 0.173

Gnomad4 ASJ AF: 0.103

Gnomad4 EAS AF: 0.0232

Gnomad4 SAS AF: 0.0917

Gnomad4 FIN AF: 0.120

Gnomad4 NFE AF: 0.115

Gnomad4 OTH AF: 0.124

Alfa AF: 0.122 Hom.: 125

Bravo AF: 0.132

Asia WGS AF: 0.0690 AC: 239 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Aug 09, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
Cadd	Benign	6.6
Dann	Benign	0.61

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs704078; hg19: chr12-89744246; COSMIC: COSV54378417; COSMIC: COSV54378417;