chr4-88046767-T-G
Variant summary
Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2
The NM_000297.4(PKD2):c.1445T>G(p.Phe482Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00218 in 1,611,890 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_000297.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -13 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.00185 AC: 282AN: 152238Hom.: 1 Cov.: 32
GnomAD3 exomes AF: 0.00204 AC: 513AN: 251372Hom.: 3 AF XY: 0.00202 AC XY: 275AN XY: 135850
GnomAD4 exome AF: 0.00221 AC: 3225AN: 1459534Hom.: 12 Cov.: 29 AF XY: 0.00221 AC XY: 1606AN XY: 726232
GnomAD4 genome AF: 0.00184 AC: 281AN: 152356Hom.: 1 Cov.: 32 AF XY: 0.00170 AC XY: 127AN XY: 74498
ClinVar
Submissions by phenotype
not provided Benign:5
PKD2: PM5, BP4, BS1, BS2 -
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This variant is associated with the following publications: (PMID: 32859249, 18257781, 27894351, 27884173, 18837007, 22995991, 22863349, 31349084) -
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not specified Benign:3
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Polycystic kidney disease 2 Uncertain:1Benign:1
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This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
Polycystic kidney disease Benign:1
The PKD2 p.Phe482Cys variant was identified in 7 of 954 proband chromosomes (frequency: 0.01) from individuals or families with ADPKD (Bataille 2011, Dedoussis 2008, Edrees 2016, Robinson 2012, Rossetti 2012, Tan 2008). The variant was also identified in the following databases: dbSNP (ID: rs75762896) as With other allele, ClinVar (classified as benign by Invitae; as likely benign by Prevention), Clinvitae , LOVD 3.0, ADPKD Mutation Database (classified as likely neutral). The variant was not identified in the COGR, or PKD1-LOVD databases. The variant was identified in control databases in 548 of 277128 chromosomes (3 homozygous) at a frequency of 0.002 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). Observations by population include African in 7 of 24034 chromosomes (freq: 0.0003), “Other” in 38 of 6462 chromosomes (freq: 0.01), Latino in 67 of 34416 chromosomes (freq: 0.002), EuropeanNon-Finnish in 302 of 126624 chromosomes (freq: 0.002), AshkenaziJewish in 102 of 10152 chromosomes (freq: 0.01), EuropeanFinnish in 3 of 25792 chromosomes (freq: 0.0001), and SouthAsian in 29 of 30782 chromosomes (freq: 0.001); it was not observed in the EastAsian population. The p.Phe482 residue is conserved in mammals but not in more distantly related organisms, and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. 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. The variant was identified with a co-occurring pathogenic PKD1 variant (IVS21–2delAG), increasing the likelihood that the p.Phe482Cys variant does not have clinical significance (Dedoussis 2008). 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
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at