chr12-89349446-A-G

Variant names:

• chr12-89349446-A-G
• rs704075
• NM_001946.4:c.954T>C

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Moderate BP6_Moderate BP7 BS1 BS2

The NM_001946.4(DUSP6):​c.954T>C​(p.Asp318Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00203 in 1,614,148 control chromosomes in the GnomAD database, including 76 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.011 (38 hom., cov: 32)
  • Exomes 𝑓: 0.0011 (38 hom.)
• Consequence: DUSP6 NM_001946.4 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.611
• Publications: 15 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: Labcorp Genetics (formerly Invitae), Ambry Genetics

POC1B-DUSP6 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.4).
• BP6: Variant 12-89349446-A-G is Benign according to our data. Variant chr12-89349446-A-G is described in ClinVar as Benign. ClinVar VariationId is 783132.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=0.611 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0111 (1683/152304) while in subpopulation AFR AF = 0.0385 (1601/41550). AF 95% confidence interval is 0.037. There are 38 homozygotes in GnomAd4. There are 768 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1683 AD gene.

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.954T>C	p.Asp318Asp	synonymous	Exon 3 of 3	NP_001937.2
	DUSP6	NM_022652.4		c.516T>C	p.Asp172Asp	synonymous	Exon 2 of 2	NP_073143.2
	POC1B-DUSP6	NM_001425794.1		c.*44T>C		3_prime_UTR	Exon 11 of 11	NP_001412723.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DUSP6	ENST00000279488.8	TSL:1 MANE Select	c.954T>C	p.Asp318Asp	synonymous	Exon 3 of 3	ENSP00000279488.6	Q16828-1
	DUSP6	ENST00000308385.6	TSL:1	c.516T>C	p.Asp172Asp	synonymous	Exon 2 of 2	ENSP00000307835.6	Q16828-2
	DUSP6	ENST00000924807.1		c.612T>C	p.Asp204Asp	synonymous	Exon 3 of 3	ENSP00000594866.1

Frequencies

GnomAD3 genomes AF: 0.0110 AC: 1679 AN: 152186 Hom.: 38 Cov.: 32

Gnomad AFR AF: 0.0385

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00393

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00718

GnomAD4 exome AF: 0.00109 AC: 1597 AN: 1461844 Hom.: 38 Cov.: 31 AF XY: 0.000939 AC XY: 683 AN XY: 727220

African (AFR) AF: 0.0382 AC: 1280 AN: 33480

American (AMR) AF: 0.00174 AC: 78 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000348 AC: 3 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53410

Middle Eastern (MID) AF: 0.00191 AC: 11 AN: 5768

European-Non Finnish (NFE) AF: 0.0000701 AC: 78 AN: 1111972

Other (OTH) AF: 0.00243 AC: 147 AN: 60396

GnomAD4 genome AF: 0.0111 AC: 1683 AN: 152304 Hom.: 38 Cov.: 32 AF XY: 0.0103 AC XY: 768 AN XY: 74478

African (AFR) AF: 0.0385 AC: 1601 AN: 41550

American (AMR) AF: 0.00392 AC: 60 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0000882 AC: 6 AN: 68024

Other (OTH) AF: 0.00710 AC: 15 AN: 2112

Alfa AF: 0.00432 Hom.: 6

Bravo AF: 0.0131

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.40
CADD	Benign	8.0
PhyloP100		0.61

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs704075; hg19: chr12-89743223;