16-2104572-A-G
Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 0P and 3B. BP4_ModerateBS2_Supporting
The NM_001009944.3(PKD1):āc.8087T>Cā(p.Leu2696Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000244 in 1,593,812 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā ). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L2696R) has been classified as Likely benign.
Frequency
Consequence
NM_001009944.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -3 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
PKD1 | NM_001009944.3 | c.8087T>C | p.Leu2696Pro | missense_variant | Exon 22 of 46 | ENST00000262304.9 | NP_001009944.3 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.000268 AC: 39AN: 145590Hom.: 0 Cov.: 20
GnomAD3 exomes AF: 0.000158 AC: 27AN: 170576Hom.: 0 AF XY: 0.000184 AC XY: 17AN XY: 92332
GnomAD4 exome AF: 0.000242 AC: 350AN: 1448110Hom.: 0 Cov.: 30 AF XY: 0.000230 AC XY: 166AN XY: 720204
GnomAD4 genome AF: 0.000268 AC: 39AN: 145702Hom.: 0 Cov.: 20 AF XY: 0.000254 AC XY: 18AN XY: 70986
ClinVar
Submissions by phenotype
Polycystic kidney disease, adult type Uncertain:1
The PKD1 c.8087T>C; p.Leu2696Pro variant (rs201238819) is reported in the literature in an individual affected with autosomal dominant polycystic kidney disease, but it was not considered to be disease-causing (Rossetti 2007). This variant is found in the non-Finnish European population with an overall allele frequency of 0.04% (33/84186 alleles) in the Genome Aggregation Database. The leucine at codon 2696 is not conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is tolerated. However, due to limited information, the clinical significance of the p.Leu2696Pro variant is uncertain at this time. References: Rossetti S et al. Comprehensive molecular diagnostics in autosomal dominant polycystic kidney disease. J Am Soc Nephrol. 2007 Jul;18(7):2143-60. -
Polycystic kidney disease Uncertain:1
The PKD1 p.Leu2696Pro variant was identified in 1 of 404 proband chromosomes (frequency: 0.002) from individuals or families with ADPKD however this variant was not considered disease causing because of the highly nonconservative nature of this site in orthologs (Rossetti 2007). This variant was also identified in the ADPKD Mutation Database (classified as likely neutral by Athena Diagnostics). The variant was not identified in LOVD 3.0 or PKD1-LOVD databases. The variant was identified in control databases in 25 of 164086 chromosomes at a frequency of 0.0002 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: European Non-Finnish in 25 of 66866 chromosomes (freq: 0.0004), while the variant was not observed in the African, Other, Latino, Ashkenazi Jewish, East Asian, European Finnish, and South Asian populations. In addition we cannot be certain that data from control databases is specific to PKD1 and not from one of the six PKD1 pseudogenes. An alternative substitution at this position resulting in a different amino acid change (c.8087T>G, p.Leu2696Arg) was identified by our laboratory and classified as benign (this is the substitution recorded for this position in dbSNP (rs201238819) and ClinVar). The p.Leu2696 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at