NM_001009944.3:c.7544G>A
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM1BP6BS2_Supporting
The NM_001009944.3(PKD1):c.7544G>A(p.Arg2515Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000273 in 1,610,104 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R2515P) has been classified as Uncertain significance.
Frequency
Consequence
NM_001009944.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 0 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
PKD1 | NM_001009944.3 | c.7544G>A | p.Arg2515Gln | missense_variant | Exon 19 of 46 | ENST00000262304.9 | NP_001009944.3 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000526 AC: 8AN: 152194Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000123 AC: 3AN: 244256Hom.: 0 AF XY: 0.00000748 AC XY: 1AN XY: 133626
GnomAD4 exome AF: 0.0000247 AC: 36AN: 1457910Hom.: 0 Cov.: 33 AF XY: 0.0000303 AC XY: 22AN XY: 725262
GnomAD4 genome AF: 0.0000526 AC: 8AN: 152194Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3AN XY: 74336
ClinVar
Submissions by phenotype
not specified Uncertain:1
Variant summary: PKD1 c.7544G>A (p.Arg2515Gln) results in a conservative amino acid change located in the REJ domain (IPR014010) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 244256 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.7544G>A in individuals affected with PKD1-Biallelic Autosomal Recessive Polycystic Kidney Disease and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 3357037). Based on the evidence outlined above, the variant was classified as uncertain significance. -
PKD1-related disorder Uncertain:1
The PKD1 c.7544G>A variant is predicted to result in the amino acid substitution p.Arg2515Gln. To our knowledge, this variant has not been reported in the literature. The p.Arg2515 residue is a weakly conserved amino acid. This variant is reported in 0.0042% of alleles in individuals of African descent in gnomAD. Of note, a different substitution at the same codon, defined as c.7544G>C (p.Arg2515Pro), was reported in an individual with autosomal dominant polycystic kidney disease (ADPKD), but the clinical significance was uncertain (Xu et al. 2018. PubMed ID: 29529603). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -
Polycystic kidney disease, adult type Benign:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at