rs748654180
Variant summary
Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_ModerateBP6BS2
The NM_000297.4(PKD2):c.356G>A(p.Arg119His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000672 in 1,517,964 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 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. R119P) has been classified as Uncertain significance.
Frequency
Consequence
NM_000297.4 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Benign. Variant got -7 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PKD2 | NM_000297.4 | c.356G>A | p.Arg119His | missense_variant | 1/15 | ENST00000237596.7 | |
PKD2 | XM_011532028.3 | c.356G>A | p.Arg119His | missense_variant | 1/14 | ||
PKD2 | NR_156488.2 | n.455G>A | non_coding_transcript_exon_variant | 1/14 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PKD2 | ENST00000237596.7 | c.356G>A | p.Arg119His | missense_variant | 1/15 | 1 | NM_000297.4 | P1 | |
ENST00000662475.1 | n.112+277C>T | intron_variant, non_coding_transcript_variant |
Frequencies
GnomAD3 genomes ? AF: 0.0000857 AC: 13AN: 151658Hom.: 1 Cov.: 32
GnomAD3 exomes AF: 0.0000983 AC: 12AN: 122048Hom.: 0 AF XY: 0.0000598 AC XY: 4AN XY: 66856
GnomAD4 exome AF: 0.0000651 AC: 89AN: 1366306Hom.: 0 Cov.: 35 AF XY: 0.0000623 AC XY: 42AN XY: 674160
GnomAD4 genome ? AF: 0.0000857 AC: 13AN: 151658Hom.: 1 Cov.: 32 AF XY: 0.0000945 AC XY: 7AN XY: 74088
ClinVar
Submissions by phenotype
Polycystic kidney disease 2 Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Dec 07, 2021 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 13, 2018 | 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. - |
Polycystic kidney disease Benign:1
Likely benign, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The PKD2 p.Arg119His variant was identified in 2 of 460 proband chromosomes (frequency: 0.004) from individuals or families with ADPKD (Rossetti 2012).The variant was also identified ADPKD Mutation Database (classified as likely neutral). The variant was not identified in dbSNP, Clinvitae, the ClinVar, GeneInsight COGR and PKD2-LOVD databases. The p.Arg119 residue is conserved in mammals and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) 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 although we would lean towards a more benign role for this variant. This variant is classified as likely benign. - |
Autosomal dominant polycystic kidney disease Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Dec 10, 2023 | - - |
not provided Benign:1
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Oct 09, 2023 | See Variant Classification Assertion Criteria. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at