Genetic Variant NM_000278.5:c.867C>G (chr10-100809184-C-G) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 1P and 13B. PP2BP4_StrongBP6BS1BS2

The NM_000278.5(PAX2):c.867C>G(p.Asn289Lys) variant causes a missense change. The variant allele was found at a frequency of 0.000159 in 1,613,818 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N289D) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00015 ( 0 hom. )

Consequence

PAX2
NM_000278.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:4

Conservation

PhyloP100: 3.90

Publications

1 publications found

Variant links:

Genes affected

PAX2 (HGNC:8616): (paired box 2) PAX2 encodes paired box gene 2, one of many human homologues of the Drosophila melanogaster gene prd. The central feature of this transcription factor gene family is the conserved DNA-binding paired box domain. PAX2 is believed to be a target of transcriptional supression by the tumor suppressor gene WT1. Mutations within PAX2 have been shown to result in optic nerve colobomas and renal hypoplasia. Alternative splicing of this gene results in multiple transcript variants. [provided by RefSeq, Dec 2014]

PAX2 Gene-Disease associations (from GenCC):

focal segmental glomerulosclerosis 7
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
renal coloboma syndrome
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Orphanet
familial idiopathic steroid-resistant nephrotic syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

PAX2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 28 curated pathogenic missense variants (we use a threshold of 10). The gene has 3 curated benign missense variants. Gene score misZ: 1.4895 (below the threshold of 3.09). Trascript score misZ: 1.8687 (below the threshold of 3.09). GenCC associations: The gene is linked to renal coloboma syndrome, focal segmental glomerulosclerosis 7, familial idiopathic steroid-resistant nephrotic syndrome.

BP4

Computational evidence support a benign effect (MetaRNN=0.027373105).

BP6

Variant 10-100809184-C-G is Benign according to our data. Variant chr10-100809184-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 534188.

BS1

Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.000154 (225/1461614) while in subpopulation MID AF = 0.00416 (24/5768). AF 95% confidence interval is 0.00287. There are 0 homozygotes in GnomAdExome4. There are 117 alleles in the male GnomAdExome4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 31 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000278.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PAX2	NM_000278.5	MANE Select	c.867C>G	p.Asn289Lys	missense	Exon 7 of 10	NP_000269.3
PAX2	NM_003990.5		c.936C>G	p.Asn312Lys	missense	Exon 8 of 11	NP_003981.3
PAX2	NM_001304569.2		c.960C>G	p.Asn320Lys	missense	Exon 8 of 11	NP_001291498.1	A0A9L9PYK3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PAX2	ENST00000355243.8	TSL:1 MANE Select	c.867C>G	p.Asn289Lys	missense	Exon 7 of 10	ENSP00000347385.3	Q02962-3
PAX2	ENST00000370296.6	TSL:1	c.867C>G	p.Asn289Lys	missense	Exon 7 of 11	ENSP00000359319.3	Q02962-4
PAX2	ENST00000554172.2	TSL:1	c.855C>G	p.Asn285Lys	missense	Exon 6 of 7	ENSP00000452489.2	G3V5S4

Frequencies

GnomAD3 genomes

AF:

0.000204

AC:

AN:

152204

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000458

Gnomad ASJ

AF:

0.00317

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000132

Gnomad OTH

AF:

0.000957

GnomAD2 exomes

AF:

0.000255

AC:

AN:

251448

AF XY:

0.000287

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000231

Gnomad ASJ exome

AF:

0.00327

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000176

Gnomad OTH exome

AF:

0.000326

GnomAD4 exome

AF:

0.000154

AC:

225

AN:

1461614

Hom.:

Cov.:

AF XY:

0.000161

AC XY:

117

AN XY:

727126

show subpopulations

African (AFR)

AF:

0.000179

AC:

AN:

33466

American (AMR)

AF:

0.000291

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00268

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.0000696

AC:

AN:

86254

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53382

Middle Eastern (MID)

AF:

0.00416

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000765

AC:

AN:

1111806

Other (OTH)

AF:

0.000348

AC:

AN:

60384

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.448

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000204

AC:

AN:

152204

Hom.:

Cov.:

AF XY:

0.000188

AC XY:

AN XY:

74350

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41442

American (AMR)

AF:

0.000458

AC:

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.00317

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5200

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00316

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000132

AC:

AN:

68038

Other (OTH)

AF:

0.000957

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000608

Hom.:

Bravo

AF:

0.000268

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000465

AC:

ExAC

AF:

0.000264

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.000356

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Inborn genetic diseases (1)

not specified (1)

PAX2-related disorder (1)

Renal coloboma syndrome;C4014925:Focal segmental glomerulosclerosis 7 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.35

BayesDel_addAF

Benign

-0.11

BayesDel_noAF

Benign

-0.10

CADD

Uncertain

(source)

DANN

Benign

0.95

DEOGEN2

Benign

0.40

Eigen

Benign

-0.039

Eigen_PC

Benign

0.10

FATHMM_MKL

Uncertain

0.97

LIST_S2

Uncertain

0.97

M_CAP

Benign

0.079

MetaRNN

Benign

0.027

MetaSVM

Uncertain

0.63

MutationAssessor

Uncertain

2.1

PhyloP100

3.9

PrimateAI

Uncertain

0.74

PROVEAN

Uncertain

-2.7

REVEL

Benign

0.041

Sift

Benign

0.059

Sift4G

Benign

0.96

Polyphen

0.20

Vest4

0.56

MutPred

0.29

Gain of ubiquitination at N312 (P = 0.0011)

MVP

0.90

MPC

0.69

ClinPred

0.064

GERP RS

4.5

Varity_R

0.24

gMVP

0.70

Mutation Taster

=76/24

polymorphism

(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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over