12-89351049-A-G

Position:

• chr12-89351049-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001946.4(DUSP6):​c.401-24T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.114 in 1,550,784 control chromosomes in the GnomAD database, including 10,712 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). There are indicators that this mutation may affect the branch point..

• Frequency:
  • Genomes: 𝑓 0.12 (1243 hom., cov: 32)
  • Exomes 𝑓: 0.11 (9469 hom.)
• Consequence: DUSP6 NM_001946.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.148

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]

ENSG00000274021 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: This place is a probable branch point but likely benign (scored 2 / 10). Computational evidence support a benign effect (MetaRNN=0.0020593107).
• BP6: Variant 12-89351049-A-G is Benign according to our data. Variant chr12-89351049-A-G is described in ClinVar as [Benign]. Clinvar id is 1292720.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 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	Protein	UniProt
DUSP6	NM_001946.4	c.401-24T>C		intron_variant		ENST00000279488.8	NP_001937.2
DUSP6	NM_022652.4	c.400+591T>C		intron_variant			NP_073143.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DUSP6	ENST00000279488.8	c.401-24T>C		intron_variant		1	NM_001946.4	ENSP00000279488.6

Frequencies

GnomAD3 genomes AF: 0.125 AC: 18994 AN: 152086 Hom.: 1241 Cov.: 32

Gnomad AFR AF: 0.140

Gnomad AMI AF: 0.250

Gnomad AMR AF: 0.173

Gnomad ASJ AF: 0.103

Gnomad EAS AF: 0.0229

Gnomad SAS AF: 0.0908

Gnomad FIN AF: 0.121

Gnomad MID AF: 0.114

Gnomad NFE AF: 0.115

Gnomad OTH AF: 0.124

GnomAD3 exomes AF: 0.118 AC: 18738 AN: 159412 Hom.: 1272 AF XY: 0.114 AC XY: 9832 AN XY: 86480

Gnomad AFR exome AF: 0.145

Gnomad AMR exome AF: 0.189

Gnomad ASJ exome AF: 0.105

Gnomad EAS exome AF: 0.0235

Gnomad SAS exome AF: 0.0974

Gnomad FIN exome AF: 0.114

Gnomad NFE exome AF: 0.113

Gnomad OTH exome AF: 0.125

GnomAD4 exome AF: 0.113 AC: 158297 AN: 1398580 Hom.: 9469 Cov.: 31 AF XY: 0.112 AC XY: 77413 AN XY: 691374

Gnomad4 AFR exome AF: 0.137

Gnomad4 AMR exome AF: 0.186

Gnomad4 ASJ exome AF: 0.108

Gnomad4 EAS exome AF: 0.0237

Gnomad4 SAS exome AF: 0.0965

Gnomad4 FIN exome AF: 0.108

Gnomad4 NFE exome AF: 0.115

Gnomad4 OTH exome AF: 0.114

GnomAD4 genome AF: 0.125 AC: 19014 AN: 152204 Hom.: 1243 Cov.: 32 AF XY: 0.125 AC XY: 9283 AN XY: 74420

Gnomad4 AFR AF: 0.140

Gnomad4 AMR AF: 0.173

Gnomad4 ASJ AF: 0.103

Gnomad4 EAS AF: 0.0230

Gnomad4 SAS AF: 0.0913

Gnomad4 FIN AF: 0.121

Gnomad4 NFE AF: 0.115

Gnomad4 OTH AF: 0.124

Alfa AF: 0.109 Hom.: 854

Bravo AF: 0.131

TwinsUK AF: 0.107 AC: 397

ALSPAC AF: 0.108 AC: 415

ESP6500AA AF: 0.126 AC: 551

ESP6500EA AF: 0.111 AC: 950

ExAC AF: 0.0786 AC: 9002

Asia WGS AF: 0.0690 AC: 239 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 09, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.82	T
BayesDel_noAF	Benign	-0.81
CADD	Benign	12
DANN	Benign	0.51
DEOGEN2	Benign	0.0071	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.050	N
LIST_S2	Uncertain	0.90	D
MetaRNN	Benign	0.0021	T
MetaSVM	Benign	-0.91	T
PROVEAN	Benign	0.48	N
REVEL	Benign	0.093
Sift	Uncertain	0.017	D
Sift4G	Uncertain	0.018	D
Vest4		0.019
ClinPred		0.0026	T
GERP RS		-3.0
BranchPoint Hunter		2.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs808820; hg19: chr12-89744826;