rs76012218
Variant summary
Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2
The NM_138694.4(PKHD1):c.888A>T(p.Pro296Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00162 in 1,581,134 control chromosomes in the GnomAD database, including 33 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).
Frequency
Consequence
NM_138694.4 synonymous
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -21 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
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PKHD1 | ENST00000371117.8 | c.888A>T | p.Pro296Pro | synonymous_variant | Exon 13 of 67 | 1 | NM_138694.4 | ENSP00000360158.3 | ||
PKHD1 | ENST00000340994.4 | c.888A>T | p.Pro296Pro | synonymous_variant | Exon 13 of 61 | 5 | ENSP00000341097.4 |
Frequencies
GnomAD3 genomes AF: 0.00854 AC: 1244AN: 145596Hom.: 22 Cov.: 23
GnomAD3 exomes AF: 0.00239 AC: 600AN: 250654Hom.: 7 AF XY: 0.00194 AC XY: 263AN XY: 135490
GnomAD4 exome AF: 0.000911 AC: 1308AN: 1435460Hom.: 11 Cov.: 28 AF XY: 0.000811 AC XY: 580AN XY: 715048
GnomAD4 genome AF: 0.00857 AC: 1249AN: 145674Hom.: 22 Cov.: 23 AF XY: 0.00861 AC XY: 609AN XY: 70742
ClinVar
Submissions by phenotype
Autosomal recessive polycystic kidney disease Benign:3
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -
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not provided Benign:2
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not specified Benign:1
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Polycystic kidney disease Benign:1
The PKHD1 p.Pro296= variant was not identified in the literature nor was it identified in the GeneInsight-COGR, LOVD 3.0, databases. The variant was identified in dbSNP (ID: rs76012218) as With Benign allele, ClinVar (classified as benign by Invitae and Prevention Genetics), RWTH AAachen University ARPKD, databases. The variant was identified in control databases in 809 of 274254 chromosomes (13 homozygous) at a frequency of 0.003 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). Breakdown of the observations by population include African in 717 of 23442 chromosomes (freq: 0.03), Other in 13 of 6372 chromosomes (freq: 0.002), Latino in 57 of 34292 chromosomes (freq: 0.002), European in 19 of 125570 chromosomes (freq: 0.0002), Ashkenazi Jewish in 2 of 10134 chromosomes (freq: 0.0002), and South Asian in 1 of 30782 chromosomes (freq: 0.00003), while the variant was not observed in the East Asian, Finnish, populations. The p.Pro296= variant is not expected to have clinical significance because it does not result in a change of amino acid and is not located in a known consensus splice site. The variant occurs outside of the splicing consensus sequence and 1 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at