4-88065496-G-C
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000297.4(PKD2):c.2240+1G>C variant causes a splice donor, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,392 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Consequence
NM_000297.4 splice_donor, intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461392Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 727046
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Polycystic kidney disease Pathogenic:1
The PKD2 c.2240+1G>C variant was identified in the literature in 1 of 440 proband chromosomes (freq: 0.002) from individuals or families with ADPKD (Hwang 2016) for which it was classified as pathogenic. This variant was not identified in dbSNP, Clinvitae, ClinVar, GeneInsight-COGR, the ADPKD Mutation Database, PKD2-LOVD, the 1000 Genomes Project, the NHLBI GO Exome Sequencing Project and the Exome Aggregation Consortium database (August 8, 2016). In the ADPKD database and PKD2 (LOVD) databases alternate substitutions at the c.2240+1 position are classified as pathogenic. The c.2240+1G>C variant is predicted to cause abnormal splicing because the nucleotide substitution occurs in the invariant region of the splice consensus sequence. In addition, 5 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict the abolishment of the 5’ splice site. In summary, based on the above information, this variant meets our laboratory’s criteria to be classified as pathogenic. -
Polycystic kidney disease 2 Pathogenic:1
PVS1, PM2_Supporting, PM5, PP3 -
not provided Pathogenic:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at