rs556575921

Positions:

chr16-2103822-A-C

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_StrongBP6_Very_StrongBP7BS2

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

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: -4.73

Variant links:

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]

PKD1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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 GnomAdExome4 at 139 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PKD1	NM_001009944.3 linkuse as main transcript	c.8235T>G	p.Ser2745=	synonymous_variant	23/46	ENST00000262304.9	NP_001009944.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PKD1	ENST00000262304.9 linkuse as main transcript	c.8235T>G	p.Ser2745=	synonymous_variant	23/46	1	NM_001009944.3	ENSP00000262304	P5	P98161-1

Frequencies

GnomAD3 genomes

AF:

0.000920

AC:

138

AN:

149972

Hom.:

Cov.:

show subpopulations

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:

AN:

246932

Hom.:

AF XY:

0.000156

AC XY:

AN XY:

134634

show subpopulations

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.:

Cov.:

AF XY:

0.0000841

AC XY:

AN XY:

725012

show subpopulations

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.:

Cov.:

AF XY:

0.000888

AC XY:

AN XY:

73228

show subpopulations

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.:

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

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) â€šÃ„ÃºWith Likely benign alleleâ€šÃ„Ã¹, 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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over