12-89351049-A-G

Variant names:

• chr12-89351049-A-G
• rs808820
• NM_001946.4:c.401-24T>C

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 7 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)

ENSG00000274021 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: This position, referring to a specific DNA site, is a probable branch point but is likely benign (scored 2 / 10, using the threshold of <=3). The score ranges from 0 to 10, with values ≤3 considered benign and >5 classified as pathogenic. 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 VariationId 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 rank	MANE	Protein	UniProt
DUSP6	NM_001946.4	c.401-24T>C		intron_variant	Intron 1 of 2	ENST00000279488.8	NP_001937.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DUSP6	ENST00000279488.8	c.401-24T>C		intron_variant	Intron 1 of 2	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

GnomAD2 exomes AF: 0.118 AC: 18738 AN: 159412 AF XY: 0.114

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 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

African (AFR) AF: 0.137 AC: 4401 AN: 32222

American (AMR) AF: 0.186 AC: 6792 AN: 36614

Ashkenazi Jewish (ASJ) AF: 0.108 AC: 2719 AN: 25236

East Asian (EAS) AF: 0.0237 AC: 880 AN: 37174

South Asian (SAS) AF: 0.0965 AC: 7821 AN: 81018

European-Finnish (FIN) AF: 0.108 AC: 4082 AN: 37648

Middle Eastern (MID) AF: 0.0970 AC: 515 AN: 5310

European-Non Finnish (NFE) AF: 0.115 AC: 124406 AN: 1084920

Other (OTH) AF: 0.114 AC: 6681 AN: 58438

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

African (AFR) AF: 0.140 AC: 5821 AN: 41518

American (AMR) AF: 0.173 AC: 2643 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.103 AC: 356 AN: 3468

East Asian (EAS) AF: 0.0230 AC: 119 AN: 5178

South Asian (SAS) AF: 0.0913 AC: 441 AN: 4832

European-Finnish (FIN) AF: 0.121 AC: 1277 AN: 10596

Middle Eastern (MID) AF: 0.112 AC: 33 AN: 294

European-Non Finnish (NFE) AF: 0.115 AC: 7835 AN: 67998

Other (OTH) AF: 0.124 AC: 261 AN: 2110

Alfa AF: 0.115 Hom.: 2434

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

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

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_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
PhyloP100		-0.15
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
PromoterAI		-0.0024	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=158/42	polymorphism (auto)

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

Other links and lift over

dbSNP: rs808820; hg19: chr12-89744826;