rs78738655

Variant names:

• chr10-100824660-C-T
• rs78738655
• NM_000278.5:c.932C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 1P and 13B. PP2 BP4_Strong BP6 BS1 BS2

The NM_000278.5(PAX2):​c.932C>T​(p.Ala311Val) variant causes a missense change. The variant allele was found at a frequency of 0.000222 in 1,607,932 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. A311A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0011 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00013 (1 hom.)
• Consequence: PAX2 NM_000278.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1 B:2 O:1
• Conservation: PhyloP100: 6.00
• Publications: 4 publications found

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

ENSG00000295657 (HGNC:):

ACMG classification

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 familial idiopathic steroid-resistant nephrotic syndrome, renal coloboma syndrome, focal segmental glomerulosclerosis 7.
• BP4: Computational evidence support a benign effect (MetaRNN=0.011975735).
• BP6: Variant 10-100824660-C-T is Benign according to our data. Variant chr10-100824660-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 156301.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00115 (175/152204) while in subpopulation AFR AF = 0.00412 (171/41518). AF 95% confidence interval is 0.00361. There are 0 homozygotes in GnomAd4. There are 89 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High AC in GnomAd4 at 175 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PAX2	NM_000278.5	MANE Select	c.932C>T	p.Ala311Val	missense	Exon 8 of 10	NP_000269.3
	PAX2	NM_003990.5		c.1001C>T	p.Ala334Val	missense	Exon 9 of 11	NP_003981.3
	PAX2	NM_001304569.2		c.1025C>T	p.Ala342Val	missense	Exon 9 of 11	NP_001291498.1	A0A9L9PYK3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PAX2	ENST00000355243.8	TSL:1 MANE Select	c.932C>T	p.Ala311Val	missense	Exon 8 of 10	ENSP00000347385.3	Q02962-3
	PAX2	ENST00000370296.6	TSL:1	c.932C>T	p.Ala311Val	missense	Exon 8 of 11	ENSP00000359319.3	Q02962-4
	PAX2	ENST00000707079.1		c.1001C>T	p.Ala334Val	missense	Exon 9 of 11	ENSP00000516730.1	A0A9L9PXU6

Frequencies

GnomAD3 genomes AF: 0.00115 AC: 175 AN: 152086 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00413

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000414 AC: 104 AN: 251442 AF XY: 0.000287

Gnomad AFR exome AF: 0.00535

Gnomad AMR exome AF: 0.000376

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000125 AC: 182 AN: 1455728 Hom.: 1 Cov.: 31 AF XY: 0.000104 AC XY: 75 AN XY: 724486

African (AFR) AF: 0.00434 AC: 145 AN: 33374

American (AMR) AF: 0.000425 AC: 19 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26094

East Asian (EAS) AF: 0.0000756 AC: 3 AN: 39676

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86140

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53380

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00000271 AC: 3 AN: 1106388

Other (OTH) AF: 0.000166 AC: 10 AN: 60190

GnomAD4 genome AF: 0.00115 AC: 175 AN: 152204 Hom.: 0 Cov.: 31 AF XY: 0.00120 AC XY: 89 AN XY: 74430

African (AFR) AF: 0.00412 AC: 171 AN: 41518

American (AMR) AF: 0.000131 AC: 2 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.00 AC: 0 AN: 4806

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

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68008

Other (OTH) AF: 0.000473 AC: 1 AN: 2114

Alfa AF: 0.000598 Hom.: 0

Bravo AF: 0.00148

ESP6500AA AF: 0.00477 AC: 21

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000420 AC: 51

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (2)
-	-	1	PAX2-related disorder (1)
-	-	1	Renal coloboma syndrome;C4014925:Focal segmental glomerulosclerosis 7 (1)
1	-	-	Retinal dystrophy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.35
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Benign	0.27	T
Eigen	Uncertain	0.19
Eigen_PC	Uncertain	0.26
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.94	D
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.012	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	1.5	L
PhyloP100		6.0
PrimateAI	Pathogenic	0.80	T
PROVEAN	Benign	-2.0	N
REVEL	Benign	0.18
Sift	Benign	0.12	T
Sift4G	Benign	0.21	T
Polyphen		0.91	P
Vest4		0.70
MVP		0.57
MPC		0.31
ClinPred		0.067	T
GERP RS		4.1
Varity_R		0.20
gMVP		0.62
Mutation Taster		=67/33	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs78738655; hg19: chr10-102584417;