dbSNP rs121918261: POU6F2:p.Gln220His (chr7-39339703-G-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 3P and 1B. PM2PP5BP4

The NM_001370959.1(POU6F2):c.660G>T(p.Gln220His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

POU6F2
NM_001370959.1 missense

Scores

Clinical Significance

Pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 2.21

Publications

0 publications found

Variant links:

Genes affected

POU6F2 (HGNC:21694): (POU class 6 homeobox 2) This gene encodes a member of the POU protein family characterized by the presence of a bipartite DNA binding domain, consisting of a POU-specific domain and a homeodomain, separated by a variable polylinker. The DNA binding domain may bind to DNA as monomers or as homo- and/or heterodimers, in a sequence-specific manner. The POU family members are transcriptional regulators, many of which are known to control cell type-specific differentiation pathways. This gene is a tumor suppressor involved in Wilms tumor (WT) predisposition. Alternatively spliced transcript variants encoding distinct isoforms have been found for this gene.[provided by RefSeq, Oct 2009]

POU6F2 Gene-Disease associations (from GenCC):

Wilms tumor 5
Inheritance: Unknown Classification: LIMITED Submitted by: Ambry Genetics

POU6F2 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 7-39339703-G-T is Pathogenic according to our data. Variant chr7-39339703-G-T is described in ClinVar as Pathogenic. ClinVar VariationId is 1871.Status of the report is no_assertion_criteria_provided, 0 stars.

BP4

Computational evidence support a benign effect (MetaRNN=0.22789556). . Strength limited to SUPPORTING due to the PP5.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001370959.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
POU6F2	NM_001370959.1	MANE Select	c.660G>T	p.Gln220His	missense	Exon 5 of 10	NP_001357888.1
POU6F2	NM_007252.4		c.573G>T	p.Gln191His	missense	Exon 6 of 11	NP_009183.3
POU6F2	NM_001166018.2		c.573G>T	p.Gln191His	missense	Exon 6 of 11	NP_001159490.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
POU6F2	ENST00000518318.7	TSL:1 MANE Select	c.660G>T	p.Gln220His	missense	Exon 5 of 10	ENSP00000430514.3
POU6F2	ENST00000403058.6	TSL:5	c.573G>T	p.Gln191His	missense	Exon 6 of 11	ENSP00000384004.1
POU6F2	ENST00000517348.1	TSL:2	n.1034G>T		non_coding_transcript_exon	Exon 5 of 6

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1451522

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

722184

African (AFR)

AF:

0.00

AC:

AN:

33424

American (AMR)

AF:

0.00

AC:

AN:

44500

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26012

East Asian (EAS)

AF:

0.00

AC:

AN:

39640

South Asian (SAS)

AF:

0.00

AC:

AN:

85860

European-Finnish (FIN)

AF:

0.00

AC:

AN:

46732

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5748

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1109556

Other (OTH)

AF:

0.00

AC:

AN:

60050

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

Wilms tumor 5

Pathogenic:1

Nov 01, 2004

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Uncertain

0.053

BayesDel_noAF

Benign

-0.16

CADD

Benign

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.12

Eigen

Benign

-0.22

Eigen_PC

Benign

-0.16

FATHMM_MKL

Benign

0.47

LIST_S2

Benign

0.50

M_CAP

Pathogenic

0.38

MetaRNN

Benign

0.23

MetaSVM

Uncertain

-0.16

MutationAssessor

Benign

0.0

PhyloP100

2.2

PrimateAI

Benign

0.44

PROVEAN

Benign

-0.46

REVEL

Benign

0.29

Sift

Uncertain

0.0030

Sift4G

Benign

0.14

Polyphen

0.94

Vest4

0.31

MutPred

0.23

Loss of MoRF binding (P = 0.3254)

MVP

0.87

MPC

0.12

ClinPred

0.50

GERP RS

3.4

Varity_R

0.10

gMVP

0.21

Mutation Taster

=7/93

disease causing (ClinVar)

(source)

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over