rs770087

Variant names:

• chr12-89350996-A-C
• rs770087
• NM_001946.4:c.430T>G

Your query was ambiguous. Multiple possible variants found:

• chr12-89350996-A-C
• chr12-89350996-A-T

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.430T>G​(p.Ser144Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.196 in 1,605,312 control chromosomes in the GnomAD database, including 33,213 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.24 (5176 hom., cov: 32)
  • Exomes 𝑓: 0.19 (28037 hom.)
• Consequence: DUSP6 NM_001946.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.93
• Publications: 36 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.00386253).
• BP6: Variant 12-89350996-A-C is Benign according to our data. Variant chr12-89350996-A-C is described in ClinVar as Benign. ClinVar VariationId is 1261506.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.38 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001946.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DUSP6	NM_001946.4	MANE Select	c.430T>G	p.Ser144Ala	missense	Exon 2 of 3	NP_001937.2
	POC1B-DUSP6	NM_001425794.1		c.1114-1435T>G		intron	N/A	NP_001412723.1
	POC1B-DUSP6	NM_001425795.1		c.1033-1435T>G		intron	N/A	NP_001412724.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DUSP6	ENST00000279488.8	TSL:1 MANE Select	c.430T>G	p.Ser144Ala	missense	Exon 2 of 3	ENSP00000279488.6
	DUSP6	ENST00000308385.6	TSL:1	c.400+644T>G		intron	N/A	ENSP00000307835.6
	DUSP6	ENST00000547291.1	TSL:2	c.55T>G	p.Ser19Ala	missense	Exon 1 of 2	ENSP00000449838.1

Frequencies

GnomAD3 genomes AF: 0.242 AC: 36809 AN: 151982 Hom.: 5167 Cov.: 32

Gnomad AFR AF: 0.385

Gnomad AMI AF: 0.291

Gnomad AMR AF: 0.239

Gnomad ASJ AF: 0.173

Gnomad EAS AF: 0.0291

Gnomad SAS AF: 0.167

Gnomad FIN AF: 0.156

Gnomad MID AF: 0.180

Gnomad NFE AF: 0.195

Gnomad OTH AF: 0.226

GnomAD2 exomes AF: 0.191 AC: 44941 AN: 235852 AF XY: 0.187

Gnomad AFR exome AF: 0.387

Gnomad AMR exome AF: 0.233

Gnomad ASJ exome AF: 0.183

Gnomad EAS exome AF: 0.0282

Gnomad FIN exome AF: 0.150

Gnomad NFE exome AF: 0.187

Gnomad OTH exome AF: 0.194

GnomAD4 exome AF: 0.191 AC: 278099 AN: 1453212 Hom.: 28037 Cov.: 32 AF XY: 0.190 AC XY: 137509 AN XY: 722536

African (AFR) AF: 0.384 AC: 12802 AN: 33366

American (AMR) AF: 0.235 AC: 10166 AN: 43196

Ashkenazi Jewish (ASJ) AF: 0.187 AC: 4876 AN: 26008

East Asian (EAS) AF: 0.0320 AC: 1266 AN: 39570

South Asian (SAS) AF: 0.179 AC: 15313 AN: 85774

European-Finnish (FIN) AF: 0.149 AC: 7520 AN: 50472

Middle Eastern (MID) AF: 0.170 AC: 977 AN: 5754

European-Non Finnish (NFE) AF: 0.192 AC: 213402 AN: 1108914

Other (OTH) AF: 0.196 AC: 11777 AN: 60158

GnomAD4 genome AF: 0.242 AC: 36859 AN: 152100 Hom.: 5176 Cov.: 32 AF XY: 0.237 AC XY: 17648 AN XY: 74350

African (AFR) AF: 0.385 AC: 15963 AN: 41432

American (AMR) AF: 0.239 AC: 3656 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.173 AC: 601 AN: 3470

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

South Asian (SAS) AF: 0.167 AC: 803 AN: 4820

European-Finnish (FIN) AF: 0.156 AC: 1658 AN: 10600

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

European-Non Finnish (NFE) AF: 0.195 AC: 13238 AN: 68004

Other (OTH) AF: 0.224 AC: 472 AN: 2110

Alfa AF: 0.206 Hom.: 15041

Bravo AF: 0.255

TwinsUK AF: 0.180 AC: 667

ALSPAC AF: 0.179 AC: 690

ESP6500AA AF: 0.383 AC: 1688

ESP6500EA AF: 0.198 AC: 1706

ExAC AF: 0.184 AC: 22373

Asia WGS AF: 0.123 AC: 431 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.059
BayesDel_addAF	Benign	-0.74	T
BayesDel_noAF	Benign	-0.70
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.12	T
Eigen	Benign	-0.38
Eigen_PC	Benign	-0.17
FATHMM_MKL	Benign	0.36	N
LIST_S2	Benign	0.29	T
MetaRNN	Benign	0.0039	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	1.4	L
PhyloP100		1.9
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	-0.26	N
REVEL	Benign	0.17
Sift	Benign	0.14	T
Sift4G	Uncertain	0.053	T
Polyphen		0.0	B
Vest4		0.092
MPC		0.59
ClinPred		0.012	T
GERP RS		5.0
PromoterAI		0.0099	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.19
gMVP		0.17
Mutation Taster		=96/4	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: rs770087; hg19: chr12-89744773; COSMIC: COSV107237702;