10-100781754-T-G

Variant names:

• chr10-100781754-T-G
• rs998799
• NM_000278.5:c.616+389T>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000278.5(PAX2):​c.616+389T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.268 in 152,070 control chromosomes in the GnomAD database, including 6,497 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.27 (6497 hom., cov: 32)
• Consequence: PAX2 NM_000278.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0880
• Publications: 1 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, MODERATE, SUPPORTIVE Submitted by: Orphanet, PanelApp Australia, Labcorp Genetics (formerly Invitae), G2P
• familial idiopathic steroid-resistant nephrotic syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.422 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PAX2	NM_000278.5	MANE Select	c.616+389T>G		intron	N/A	NP_000269.3
	PAX2	NM_003990.5		c.616+389T>G		intron	N/A	NP_003981.3
	PAX2	NM_001304569.2		c.709+389T>G		intron	N/A	NP_001291498.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PAX2	ENST00000355243.8	TSL:1 MANE Select	c.616+389T>G		intron	N/A	ENSP00000347385.3
	PAX2	ENST00000370296.6	TSL:1	c.616+389T>G		intron	N/A	ENSP00000359319.3
	PAX2	ENST00000554172.2	TSL:1	c.604+413T>G		intron	N/A	ENSP00000452489.2

Frequencies

GnomAD3 genomes AF: 0.268 AC: 40677 AN: 151952 Hom.: 6490 Cov.: 32

Gnomad AFR AF: 0.427

Gnomad AMI AF: 0.178

Gnomad AMR AF: 0.207

Gnomad ASJ AF: 0.229

Gnomad EAS AF: 0.00483

Gnomad SAS AF: 0.192

Gnomad FIN AF: 0.155

Gnomad MID AF: 0.367

Gnomad NFE AF: 0.230

Gnomad OTH AF: 0.273

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.268 AC: 40712 AN: 152070 Hom.: 6497 Cov.: 32 AF XY: 0.260 AC XY: 19302 AN XY: 74362

African (AFR) AF: 0.427 AC: 17698 AN: 41448

American (AMR) AF: 0.206 AC: 3156 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.229 AC: 794 AN: 3470

East Asian (EAS) AF: 0.00484 AC: 25 AN: 5164

South Asian (SAS) AF: 0.192 AC: 925 AN: 4816

European-Finnish (FIN) AF: 0.155 AC: 1636 AN: 10586

Middle Eastern (MID) AF: 0.378 AC: 111 AN: 294

European-Non Finnish (NFE) AF: 0.230 AC: 15635 AN: 67982

Other (OTH) AF: 0.270 AC: 570 AN: 2114

Alfa AF: 0.250 Hom.: 679

Bravo AF: 0.278

Asia WGS AF: 0.0980 AC: 341 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	4.4
DANN	Benign	0.37
PhyloP100		0.088
Mutation Taster		=100/0	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: rs998799; hg19: chr10-102541511;