rs41291450

Variant names:

• chr10-100750841-C-T
• rs41291450
• NM_000278.5:c.360C>T
• PAX2 p.Ala120Ala

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BS1 BS2

The NM_000278.5(PAX2):​c.360C>T​(p.Ala120Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00321 in 1,614,148 control chromosomes in the GnomAD database, including 18 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0026 (2 hom., cov: 33)
  • Exomes 𝑓: 0.0033 (16 hom.)
• Consequence: PAX2 NM_000278.5 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:6
• Conservation: PhyloP100: -6.41
• 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, SUPPORTIVE Submitted by: G2P, Orphanet, Labcorp Genetics (formerly Invitae)
• familial idiopathic steroid-resistant nephrotic syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.62).
• BP6: Variant 10-100750841-C-T is Benign according to our data. Variant chr10-100750841-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 94386.
• BP7: Synonymous conserved (PhyloP=-6.41 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00261 (398/152368) while in subpopulation NFE AF = 0.00422 (287/68034). AF 95% confidence interval is 0.00382. There are 2 homozygotes in GnomAd4. There are 185 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 398 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.360C>T	p.Ala120Ala	synonymous	Exon 3 of 10	NP_000269.3
	PAX2	NM_003990.5		c.360C>T	p.Ala120Ala	synonymous	Exon 3 of 11	NP_003981.3
	PAX2	NM_001304569.2		c.453C>T	p.Ala151Ala	synonymous	Exon 4 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.360C>T	p.Ala120Ala	synonymous	Exon 3 of 10	ENSP00000347385.3	Q02962-3
	PAX2	ENST00000370296.6	TSL:1	c.360C>T	p.Ala120Ala	synonymous	Exon 3 of 11	ENSP00000359319.3	Q02962-4
	PAX2	ENST00000554172.2	TSL:1	c.372C>T	p.Ala124Ala	synonymous	Exon 2 of 7	ENSP00000452489.2	G3V5S4

Frequencies

GnomAD3 genomes AF: 0.00261 AC: 398 AN: 152250 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.00106

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00196

Gnomad ASJ AF: 0.00374

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000827

Gnomad FIN AF: 0.00122

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00422

Gnomad OTH AF: 0.00335

GnomAD2 exomes AF: 0.00288 AC: 724 AN: 251300 AF XY: 0.00267

Gnomad AFR exome AF: 0.00129

Gnomad AMR exome AF: 0.00159

Gnomad ASJ exome AF: 0.00546

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00180

Gnomad NFE exome AF: 0.00465

Gnomad OTH exome AF: 0.00310

GnomAD4 exome AF: 0.00328 AC: 4789 AN: 1461780 Hom.: 16 Cov.: 32 AF XY: 0.00307 AC XY: 2229 AN XY: 727202

African (AFR) AF: 0.00108 AC: 36 AN: 33480

American (AMR) AF: 0.00152 AC: 68 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00555 AC: 145 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000151 AC: 13 AN: 86256

European-Finnish (FIN) AF: 0.00178 AC: 95 AN: 53356

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 0.00383 AC: 4254 AN: 1111972

Other (OTH) AF: 0.00293 AC: 177 AN: 60388

GnomAD4 genome AF: 0.00261 AC: 398 AN: 152368 Hom.: 2 Cov.: 33 AF XY: 0.00248 AC XY: 185 AN XY: 74516

African (AFR) AF: 0.00106 AC: 44 AN: 41594

American (AMR) AF: 0.00196 AC: 30 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00374 AC: 13 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.000828 AC: 4 AN: 4832

European-Finnish (FIN) AF: 0.00122 AC: 13 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00422 AC: 287 AN: 68034

Other (OTH) AF: 0.00331 AC: 7 AN: 2112

Alfa AF: 0.00378 Hom.: 0

Bravo AF: 0.00236

EpiCase AF: 0.00365

EpiControl AF: 0.00391

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	4	not provided (5)
-	-	1	not specified (1)
-	-	1	Renal coloboma syndrome;C4014925:Focal segmental glomerulosclerosis 7 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.62
CADD	Benign	0.15
DANN	Benign	0.86
PhyloP100		-6.4
Mutation Taster		=97/3	polymorphism

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs41291450;

hg19: chr10-102510598;