NM_000278.5:c.-414C>T

Variant names:

• chr10-100745847-C-T
• rs143696860
• NM_000278.5:c.-414C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Moderate BP6_Moderate BS1 BS2

The NM_000278.5(PAX2):​c.-414C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00992 in 1,126,854 control chromosomes in the GnomAD database, including 57 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0061 (6 hom., cov: 33)
  • Exomes 𝑓: 0.011 (51 hom.)
• Consequence: PAX2 NM_000278.5 5_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.133
• 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: 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.43).
• BP6: Variant 10-100745847-C-T is Benign according to our data. Variant chr10-100745847-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 1210888.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00613 (934/152276) while in subpopulation NFE AF = 0.0094 (639/67996). AF 95% confidence interval is 0.00879. There are 6 homozygotes in GnomAd4. There are 463 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 934 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.-414C>T		5_prime_UTR	Exon 1 of 10	NP_000269.3
	PAX2	NM_003990.5		c.-414C>T		5_prime_UTR	Exon 1 of 11	NP_003981.3
	PAX2	NM_003987.5		c.-414C>T		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.-414C>T		5_prime_UTR	Exon 1 of 10	ENSP00000347385.3	Q02962-3
	PAX2	ENST00000370296.6	TSL:1	c.-414C>T		5_prime_UTR	Exon 1 of 11	ENSP00000359319.3	Q02962-4
	PAX2	ENST00000707079.1		c.-414C>T		5_prime_UTR	Exon 1 of 11	ENSP00000516730.1	A0A9L9PXU6

Frequencies

GnomAD3 genomes AF: 0.00614 AC: 935 AN: 152168 Hom.: 6 Cov.: 33

Gnomad AFR AF: 0.00150

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00373

Gnomad ASJ AF: 0.00259

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0145

Gnomad MID AF: 0.00955

Gnomad NFE AF: 0.00940

Gnomad OTH AF: 0.00526

GnomAD4 exome AF: 0.0105 AC: 10241 AN: 974578 Hom.: 51 Cov.: 29 AF XY: 0.0102 AC XY: 4644 AN XY: 454306

African (AFR) AF: 0.00109 AC: 22 AN: 20264

American (AMR) AF: 0.00168 AC: 7 AN: 4170

Ashkenazi Jewish (ASJ) AF: 0.00164 AC: 19 AN: 11560

East Asian (EAS) AF: 0.00 AC: 0 AN: 15872

South Asian (SAS) AF: 0.000381 AC: 9 AN: 23614

European-Finnish (FIN) AF: 0.00937 AC: 57 AN: 6084

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2440

European-Non Finnish (NFE) AF: 0.0115 AC: 9792 AN: 853038

Other (OTH) AF: 0.00892 AC: 335 AN: 37536

GnomAD4 genome AF: 0.00613 AC: 934 AN: 152276 Hom.: 6 Cov.: 33 AF XY: 0.00622 AC XY: 463 AN XY: 74450

African (AFR) AF: 0.00149 AC: 62 AN: 41566

American (AMR) AF: 0.00366 AC: 56 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00259 AC: 9 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.0145 AC: 154 AN: 10622

Middle Eastern (MID) AF: 0.0103 AC: 3 AN: 292

European-Non Finnish (NFE) AF: 0.00940 AC: 639 AN: 67996

Other (OTH) AF: 0.00520 AC: 11 AN: 2114

Alfa AF: 0.00454 Hom.: 2

Bravo AF: 0.00538

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.43
CADD	Benign	15
DANN	Benign	0.96
PhyloP100		0.13
PromoterAI		0.050	Neutral
Mutation Taster		=300/0	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

Other links and lift over

dbSNP: rs143696860; hg19: chr10-102505604;