10-100746058-A-G

Variant names:

• chr10-100746058-A-G
• rs11190680
• NM_000278.5:c.-203A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000278.5(PAX2):​c.-203A>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.808 in 1,466,716 control chromosomes in the GnomAD database, including 480,889 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.80 (48831 hom., cov: 30)
  • Exomes 𝑓: 0.81 (432058 hom.)
• Consequence: PAX2 NM_000278.5 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.404
• Publications: 8 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

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 10-100746058-A-G is Benign according to our data. Variant chr10-100746058-A-G is described in ClinVar as Benign. ClinVar VariationId is 1250881.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.975 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PAX2	NM_000278.5	MANE Select	c.-203A>G		5_prime_UTR	Exon 1 of 10	NP_000269.3
	PAX2	NM_003990.5		c.-203A>G		5_prime_UTR	Exon 1 of 11	NP_003981.3
	PAX2	NM_003987.5		c.-203A>G		5_prime_UTR	Exon 1 of 11	NP_003978.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PAX2	ENST00000355243.8	TSL:1 MANE Select	c.-203A>G		5_prime_UTR	Exon 1 of 10	ENSP00000347385.3	Q02962-3
	PAX2	ENST00000370296.6	TSL:1	c.-203A>G		5_prime_UTR	Exon 1 of 11	ENSP00000359319.3	Q02962-4
	PAX2	ENST00000707079.1		c.-203A>G		5_prime_UTR	Exon 1 of 11	ENSP00000516730.1	A0A9L9PXU6

Frequencies

GnomAD3 genomes AF: 0.801 AC: 121344 AN: 151530 Hom.: 48787 Cov.: 30

Gnomad AFR AF: 0.755

Gnomad AMI AF: 0.827

Gnomad AMR AF: 0.815

Gnomad ASJ AF: 0.794

Gnomad EAS AF: 0.998

Gnomad SAS AF: 0.920

Gnomad FIN AF: 0.863

Gnomad MID AF: 0.790

Gnomad NFE AF: 0.793

Gnomad OTH AF: 0.778

GnomAD4 exome AF: 0.809 AC: 1064063 AN: 1315074 Hom.: 432058 Cov.: 28 AF XY: 0.811 AC XY: 522243 AN XY: 643822

African (AFR) AF: 0.741 AC: 21081 AN: 28432

American (AMR) AF: 0.842 AC: 20377 AN: 24214

Ashkenazi Jewish (ASJ) AF: 0.789 AC: 15156 AN: 19208

East Asian (EAS) AF: 0.999 AC: 36483 AN: 36502

South Asian (SAS) AF: 0.920 AC: 61764 AN: 67142

European-Finnish (FIN) AF: 0.850 AC: 27029 AN: 31812

Middle Eastern (MID) AF: 0.769 AC: 2926 AN: 3804

European-Non Finnish (NFE) AF: 0.796 AC: 835150 AN: 1049598

Other (OTH) AF: 0.811 AC: 44097 AN: 54362

GnomAD4 genome AF: 0.801 AC: 121441 AN: 151642 Hom.: 48831 Cov.: 30 AF XY: 0.809 AC XY: 59960 AN XY: 74108

African (AFR) AF: 0.755 AC: 31238 AN: 41348

American (AMR) AF: 0.815 AC: 12462 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.794 AC: 2754 AN: 3468

East Asian (EAS) AF: 0.998 AC: 5042 AN: 5052

South Asian (SAS) AF: 0.920 AC: 4417 AN: 4802

European-Finnish (FIN) AF: 0.863 AC: 9116 AN: 10566

Middle Eastern (MID) AF: 0.784 AC: 229 AN: 292

European-Non Finnish (NFE) AF: 0.793 AC: 53782 AN: 67808

Other (OTH) AF: 0.781 AC: 1648 AN: 2110

Alfa AF: 0.797 Hom.: 9720

Bravo AF: 0.793

Asia WGS AF: 0.946 AC: 3283 AN: 3472

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	8.4
DANN	Benign	0.42
PhyloP100		0.40
PromoterAI		0.023	Neutral
Mutation Taster		=300/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs11190680; hg19: chr10-102505815;