rs556575921

chr16-2103822-A-C

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_001009944.3(PKD1):c.8235T>G(p.Ser2745=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000954 in 1,457,428 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00093 (1 hom., cov: 30)
  • Exomes 𝑓: 0.000095 (1 hom.)
  • Failed GnomAD Quality Control
• Consequence: PKD1 NM_001009944.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -4.73

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]

ACMG classification

Verdict is Benign. Variant got -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.97).
• BP6: Variant 16-2103822-A-C is Benign according to our data. Variant chr16-2103822-A-C is described in ClinVar as [Likely_benign]. Clinvar id is 257016.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2103822-A-C is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-4.73 with no splicing effect.
• BS2: High AC in GnomAd at 138 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PKD1	NM_001009944.3	c.8235T>G	p.Ser2745=	synonymous_variant	23/46	ENST00000262304.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PKD1	ENST00000262304.9	c.8235T>G	p.Ser2745=	synonymous_variant	23/46	1	NM_001009944.3	P5

Frequencies

GnomAD3 genomes AF: 0.000920 AC: 138 AN: 149972 Hom.: 1 Cov.: 30

Gnomad AFR AF: 0.00328

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000132

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000214

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000296

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000198 AC: 49 AN: 246932 Hom.: 0 AF XY: 0.000156 AC XY: 21 AN XY: 134634

Gnomad AFR exome AF: 0.00258

Gnomad AMR exome AF: 0.000145

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000551

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000181

Gnomad OTH exome AF: 0.000166

GnomAD4 exome AF: 0.0000954 AC: 139 AN: 1457428 Hom.: 1 Cov.: 34 AF XY: 0.0000841 AC XY: 61 AN XY: 725012

Gnomad4 AFR exome AF: 0.00213

Gnomad4 AMR exome AF: 0.000179

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000459

Gnomad4 OTH exome AF: 0.000116

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.000926 AC: 139 AN: 150094 Hom.: 1 Cov.: 30 AF XY: 0.000888 AC XY: 65 AN XY: 73228

Gnomad4 AFR AF: 0.00329

Gnomad4 AMR AF: 0.000132

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000214

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000296

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000324 Hom.: 0

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Polycystic kidney disease, adult type Benign:1

Benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Jul 27, 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.Ser2745= variant was identified in 2 of 160 proband chromosomes (frequency: 0.0125) from individuals or families with ADPKD, and was not identified in 100 control chromosomes from healthy individuals (Watnick 1997). Affected individuals were discovered to have clusters of base pair substitutions in exons 23 and 25 in addition to the variant (c>8279T>C/M2760T, c>8282G>C/R2761P, c>8291T>C/M2764T c>8477T>C/I2826T, c>8287C>G/L2763V), and the variant segregated with disease in 1 kindred (Watnick 1997). In a study looking at the consequences of gene conversions in the PKD1 gene, pathogenicity was undetermined (Symmons 2008). The variant was also identified in dbSNP (ID: rs556575921) “With Likely benign allele”, ClinVar (classified likely benign by Prevention Genetics), LOVD 3.0 (1x), ADPKD Mutation Database (classified as highly likely pathogenic, exon 23 gene conversion (2)), and was not identified in COGR, and PKD1-LOVD databases. The variant was identified in control databases in 49 of 243470 chromosomes at a frequency of 0.0002 increasing the likelihood this could be a low frequency variant (Genome Aggregation Consortium Feb 27, 2017), being identified in the following populations: African in 39 of 14862 chromosomes (frequency: 0.003), Other in 1 of 5428 chromosomes (frequency: 0.0002), Latino in 6 of 33526 chromosomes (frequency: 0.0002), European Non-Finnish in 2 of 109758 chromosomes (frequency: 0.00002), and East Asian in 1 of 17192 chromosomes (frequency: 0.00006). In addition we cannot be certain that data from control databases is specific to PKD1 and not from one of the six PKD1 pseudogenes. The variant was identified in 1 individual with ADPKD in our laboratory, co-occurring with a pathogenic PKD2 variant (c.958C>T, p.Ala320X), increasing the likelihood the variant does not have clinical significance. The p.Ser2745= 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. 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

Benign, criteria provided, single submitter

research

Molecular Genetics of Inherited Kidney Disorders Laboratory, Garvan Institute of Medical Research

Jan 01, 2019

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Oct 02, 2020

See Variant Classification Assertion Criteria. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
Cadd	Benign	0.17
Dann	Benign	0.29

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs556575921; hg19: chr16-2153823;