rs527655141
Variant summary
Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_StrongBP6_Very_StrongBP7BS2
The NM_001009944.3(PKD1):c.2109C>T(p.His703=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000846 in 1,530,236 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 Likely benign (★★).
Frequency
Genomes: 𝑓 0.00096 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00083 ( 0 hom. )
Consequence
PKD1
NM_001009944.3 synonymous
NM_001009944.3 synonymous
Scores
2
Clinical Significance
Conservation
PhyloP100: -3.63
Genes affected
PKD1 (HGNC:9008): (polycystin 1, transient receptor potential channel interacting) This gene encodes a member of the polycystin protein family. The encoded glycoprotein contains a large N-terminal extracellular region, multiple transmembrane domains and a cytoplasmic C-tail. It is an integral membrane protein that functions as a regulator of calcium permeable cation channels and intracellular calcium homoeostasis. It is also involved in cell-cell/matrix interactions and may modulate G-protein-coupled signal-transduction pathways. It plays a role in renal tubular development, and mutations in this gene cause autosomal dominant polycystic kidney disease type 1 (ADPKD1). ADPKD1 is characterized by the growth of fluid-filled cysts that replace normal renal tissue and result in end-stage renal failure. Splice variants encoding different isoforms have been noted for this gene. Also, six pseudogenes, closely linked in a known duplicated region on chromosome 16p, have been described. [provided by RefSeq, Oct 2008]
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ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -17 ACMG points.
BP4
?
Computational evidence support a benign effect (BayesDel_noAF=-0.92).
BP6
?
Variant 16-2114914-G-A is Benign according to our data. Variant chr16-2114914-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 487359.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2114914-G-A is described in Lovd as [Likely_benign].
BP7
?
Synonymous conserved (PhyloP=-3.63 with no splicing effect.
BS2
?
High AC in GnomAd at 146 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PKD1 | NM_001009944.3 | c.2109C>T | p.His703= | synonymous_variant | 11/46 | ENST00000262304.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PKD1 | ENST00000262304.9 | c.2109C>T | p.His703= | synonymous_variant | 11/46 | 1 | NM_001009944.3 | P5 | |
PKD1 | ENST00000423118.5 | c.2109C>T | p.His703= | synonymous_variant | 11/46 | 1 | A2 | ||
PKD1 | ENST00000488185.2 | c.472+2575C>T | intron_variant | 5 | |||||
PKD1 | ENST00000568591.5 | c.*437C>T | 3_prime_UTR_variant, NMD_transcript_variant | 7/12 | 2 |
Frequencies
GnomAD3 genomes ? AF: 0.000959 AC: 146AN: 152234Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000721 AC: 77AN: 106850Hom.: 0 AF XY: 0.000643 AC XY: 36AN XY: 55962
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GnomAD4 exome AF: 0.000832 AC: 1147AN: 1377884Hom.: 0 Cov.: 30 AF XY: 0.000786 AC XY: 535AN XY: 680700
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ClinVar
Significance: Benign/Likely benign
Submissions summary: Benign:6
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Benign:3
Likely benign, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, University Medical Center Utrecht | - | - - |
Likely benign, no assertion criteria provided | clinical testing | Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) | - | - - |
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Feb 09, 2021 | This variant is associated with the following publications: (PMID: 11967008) - |
Polycystic kidney disease, adult type Benign:2
Benign, criteria provided, single submitter | clinical testing | Athena Diagnostics | Jun 09, 2017 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 05, 2021 | - - |
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.His703= variant was not identified in the literature, nor was it identified in the Clinvitae, ClinVar, GeneInsight COGR, MutDB, ADPKD Mutation, PKD1-LOVD, PKD1-LOVD 3.0 databases, or the NHLBI GO Exome Sequencing Project. The variant was identified in dbSNP (ID: rs527655141) as “NA”: in the 1000 Genomes Project in 1 of 5000 chromosomes (frequency: 0.0002): the Exome Aggregation Consortium database (August 8th 2016) in 1 of 2636 chromosomes (freq. 0004) of the European (Non-Finnish) population but not seen in the African, East Asian, European (Finnish), Latino, and South Asian populations; the genome Aggregation Database (beta, October 19th 2016) in 102 (1 homozygous) of 132868 chromosomes (freq.0.0008). However we cannot be certain that data from control databases is specific to PKD1 and not from one of the six PKD1 pseudogenes. The p.His703= variant is not expected to have clinical significance because it does not result in a change of amino acid and is not located in a known consensus splice site. In addition, in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. The variant was identified by our laboratory in a patient with ADPKD with a co-occurring pathogenic PKD1 variant (c.9240_9241del, p.Ala3082CysfsX96), increasing the likelihood that the p.His703= variant does not have clinical significance. 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
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BayesDel_noAF
Benign
Cadd
Benign
Dann
Benign
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at