rs768613812
Variant summary
Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_StrongBP6BS2_Supporting
The NM_001009944.3(PKD1):c.1643C>T(p.Ala548Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000269 in 1,560,522 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (no stars).
Frequency
Consequence
NM_001009944.3 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Likely_benign. Variant got -6 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
PKD1 | NM_001009944.3 | c.1643C>T | p.Ala548Val | missense_variant | Exon 8 of 46 | ENST00000262304.9 | NP_001009944.3 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000131 AC: 2AN: 152184Hom.: 0 Cov.: 33
GnomAD4 exome AF: 0.0000284 AC: 40AN: 1408338Hom.: 0 Cov.: 31 AF XY: 0.0000287 AC XY: 20AN XY: 697886
GnomAD4 genome AF: 0.0000131 AC: 2AN: 152184Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2AN XY: 74336
ClinVar
Submissions by phenotype
Autosomal dominant polycystic kidney disease Benign:1
The PKD1 p.Ala548Val variant was not identified in the literature nor was it identified in the Clinvitae database, the ClinVar database, GeneInsight COGR database, ADPKD Mutation Database, PKD1-LOVD, and PKD1-LOVD 3.0 (classification). The variant was identified in dbSNP (ID: rs768613812) “With unknown allele”, and in the Exome Aggregation Consortium (ExAC) database (released Jan 13, 2015) in 1 of 20960 chromosomes (frequency: 0.00005) (or 1 individual from a population of European (Non-Finnish) individuals and none from East Asian, Other, African, Latino, South Asian, or European (Finnish) individuals). The p.Ala548 residue is not conserved in mammals and the variant amino acid Val is present in rat, increasing the likelihood that this variant does not have clinical significance. Computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. 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