10-100746294-GCGATGCACCGTGAGTACCGGCGCCCGGCTCCTGTC-TGT

Position:

• chr10-100746294-GCGATGCACCGTGAGTACCGGCGCCCGGCTCCTGTC-TGT

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_000278.5(PAX2):​c.34_43+26delinsTGT variant causes a splice donor, splice donor 5th base, coding sequence, intron change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: PAX2 NM_000278.5 splice_donor, splice_donor_5th_base, coding_sequence, intron
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 8.65

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]

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 10-100746294-GCGATGCACCGTGAGTACCGGCGCCCGGCTCCTGTC-TGT is Pathogenic according to our data. Variant chr10-100746294-GCGATGCACCGTGAGTACCGGCGCCCGGCTCCTGTC-TGT is described in ClinVar as [Pathogenic]. Clinvar id is 1323415.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PAX2	NM_000278.5	c.34_43+26delinsTGT		splice_donor_variant, splice_donor_5th_base_variant, coding_sequence_variant, intron_variant	1/10	ENST00000355243.8	NP_000269.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PAX2	ENST00000355243.8	c.34_43+26delinsTGT		splice_donor_variant, splice_donor_5th_base_variant, coding_sequence_variant, intron_variant	1/10	1	NM_000278.5	ENSP00000347385	P4

Frequencies

GnomAD3 genomes Cov.: 32

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

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Revvity Omics, Revvity

May 13, 2019

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Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr10-102506051;