rs4523631

Variant names:

• chr10-100745602-C-A
• rs4523631
• NM_000278.5:c.-659C>A

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The NM_000278.5(PAX2):​c.-659C>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.8 in 238,814 control chromosomes in the GnomAD database, including 76,779 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.80 (48638 hom., cov: 31)
  • Exomes 𝑓: 0.80 (28141 hom.)
• Consequence: PAX2 NM_000278.5 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.0270
• Publications: 3 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 -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.29).
• BP6: Variant 10-100745602-C-A is Benign according to our data. Variant chr10-100745602-C-A is described in ClinVar as Benign. ClinVar VariationId is 1245518.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.-659C>A		5_prime_UTR	Exon 1 of 10	NP_000269.3
	PAX2	NM_003990.5		c.-659C>A		5_prime_UTR	Exon 1 of 11	NP_003981.3
	PAX2	NM_003987.5		c.-659C>A		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.-659C>A		5_prime_UTR	Exon 1 of 10	ENSP00000347385.3	Q02962-3
	PAX2	ENST00000707079.1		c.-659C>A		5_prime_UTR	Exon 1 of 11	ENSP00000516730.1	A0A9L9PXU6
	PAX2	ENST00000427256.6	TSL:3	c.-659C>A		5_prime_UTR	Exon 1 of 10	ENSP00000398652.2	Q5SZP1

Frequencies

GnomAD3 genomes AF: 0.798 AC: 121171 AN: 151812 Hom.: 48595 Cov.: 31

Gnomad AFR AF: 0.747

Gnomad AMI AF: 0.827

Gnomad AMR AF: 0.814

Gnomad ASJ AF: 0.794

Gnomad EAS AF: 0.998

Gnomad SAS AF: 0.920

Gnomad FIN AF: 0.862

Gnomad MID AF: 0.790

Gnomad NFE AF: 0.793

Gnomad OTH AF: 0.778

GnomAD4 exome AF: 0.802 AC: 69731 AN: 86894 Hom.: 28141 AF XY: 0.804 AC XY: 33119 AN XY: 41182

African (AFR) AF: 0.712 AC: 1395 AN: 1958

American (AMR) AF: 0.805 AC: 504 AN: 626

Ashkenazi Jewish (ASJ) AF: 0.776 AC: 1561 AN: 2012

East Asian (EAS) AF: 1.00 AC: 5773 AN: 5774

South Asian (SAS) AF: 0.928 AC: 1267 AN: 1366

European-Finnish (FIN) AF: 0.810 AC: 34 AN: 42

Middle Eastern (MID) AF: 0.748 AC: 232 AN: 310

European-Non Finnish (NFE) AF: 0.787 AC: 55687 AN: 70722

Other (OTH) AF: 0.803 AC: 3278 AN: 4084

GnomAD4 genome AF: 0.798 AC: 121265 AN: 151920 Hom.: 48638 Cov.: 31 AF XY: 0.806 AC XY: 59875 AN XY: 74248

African (AFR) AF: 0.747 AC: 30954 AN: 41446

American (AMR) AF: 0.814 AC: 12446 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.794 AC: 2755 AN: 3468

East Asian (EAS) AF: 0.998 AC: 5094 AN: 5106

South Asian (SAS) AF: 0.919 AC: 4427 AN: 4816

European-Finnish (FIN) AF: 0.862 AC: 9127 AN: 10594

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

European-Non Finnish (NFE) AF: 0.793 AC: 53838 AN: 67900

Other (OTH) AF: 0.781 AC: 1641 AN: 2102

Alfa AF: 0.801 Hom.: 6070

Bravo AF: 0.790

Asia WGS AF: 0.945 AC: 3259 AN: 3450

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	-0.29
CADD	Benign	15
DANN	Benign	0.92
PhyloP100		0.027
PromoterAI		-0.0074	Neutral

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs4523631; hg19: chr10-102505359;