rs148496347
Variant summary
Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2
The NM_001009944.3(PKD1):c.6665C>T(p.Ala2222Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00135 in 1,608,720 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A2222G) has been classified as Uncertain significance.
Frequency
Consequence
NM_001009944.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -9 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PKD1 | NM_001009944.3 | c.6665C>T | p.Ala2222Val | missense_variant | 15/46 | ENST00000262304.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PKD1 | ENST00000262304.9 | c.6665C>T | p.Ala2222Val | missense_variant | 15/46 | 1 | NM_001009944.3 | P5 |
Frequencies
GnomAD3 genomes ? AF: 0.000894 AC: 136AN: 152196Hom.: 1 Cov.: 33
GnomAD3 exomes AF: 0.000659 AC: 157AN: 238062Hom.: 0 AF XY: 0.000640 AC XY: 84AN XY: 131308
GnomAD4 exome AF: 0.00140 AC: 2042AN: 1456410Hom.: 1 Cov.: 34 AF XY: 0.00135 AC XY: 980AN XY: 724540
GnomAD4 genome ? AF: 0.000893 AC: 136AN: 152310Hom.: 1 Cov.: 33 AF XY: 0.000873 AC XY: 65AN XY: 74480
ClinVar
Submissions by phenotype
not specified Benign:2
Benign, criteria provided, single submitter | clinical testing | Athena Diagnostics | Oct 28, 2020 | - - |
Benign, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, University Medical Center Utrecht | - | - - |
Polycystic kidney disease, adult type Benign:2
Likely benign, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Sep 06, 2019 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Nov 01, 2021 | - - |
not provided Benign:2
Benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Sep 01, 2023 | PKD1: BP4, BS1, BS2 - |
Likely benign, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 11, 2021 | The c.6665C>T (p.A2222V) alteration is located in exon 15 (coding exon 15) of the PKD1 gene. This alteration results from a C to T substitution at nucleotide position 6665, causing the alanine (A) at amino acid position 2222 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Polycystic kidney disease Benign:1
Likely benign, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The PKD1, p.Ala2222Val variant was not identified in the literature nor was it identified in the Clinvitae, ClinVar, GeneInsight COGR, PKD1-LOVD and PKD1-LOVD 3.0 databases. The variant was identified in dbSNP (ID: rs148496347) as “NA”, ADPKD Mutation Database (classified as likely neutral), the 1000 Genomes Project in 4 of 5000 chromosomes (frequency: 0.0008), the NHLBI GO Exome Sequencing Project in 14 of 8480 European American alleles, the Exome Aggregation Consortium database (March 14, 2016) in 49 of 106856 chromosomes (freq. 0.0005) in the following populations: European in 48 of 57726 chromosomes (freq. 0.0008), African in 1 of 7870 chromosomes (freq. 0.0001), but was not seen in Asian, Finish, Latino and Other populations, increasing the likelihood that this may be a low frequency benign variant in certain populations of origin. In addition we cannot be certain that data from control databases is specific to PKD1 and not from one of the six PKD1 pseudogenes. The p.Ala2222 residue is conserved across mammals and other organisms, however computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest that the variant may impact the protein; this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and 2 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. - |
PKD1-related disorder Benign:1
Likely benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Dec 26, 2019 | This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at