rs149056734

Variant names:

• chr16-2102188-G-A
• rs149056734
• NM_001009944.3:c.9270C>T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001009944.3(PKD1):​c.9270C>T​(p.Val3090Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0106 in 1,507,574 control chromosomes in the GnomAD database, including 180 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0075 (5 hom., cov: 32)
  • Exomes 𝑓: 0.011 (175 hom.)
• Consequence: PKD1 NM_001009944.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 0.666

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.52).
• BP6: Variant 16-2102188-G-A is Benign according to our data. Variant chr16-2102188-G-A is described in ClinVar as [Benign]. Clinvar id is 257041.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2102188-G-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=0.666 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00747 (1135/151862) while in subpopulation NFE AF= 0.0118 (802/67998). AF 95% confidence interval is 0.0111. There are 5 homozygotes in gnomad4. There are 490 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 1135 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PKD1	NM_001009944.3	c.9270C>T	p.Val3090Val	synonymous_variant	Exon 26 of 46	ENST00000262304.9	NP_001009944.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PKD1	ENST00000262304.9	c.9270C>T	p.Val3090Val	synonymous_variant	Exon 26 of 46	1	NM_001009944.3	ENSP00000262304.4

Frequencies

GnomAD3 genomes AF: 0.00749 AC: 1136 AN: 151744 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.00222

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00518

Gnomad ASJ AF: 0.0124

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00725

Gnomad FIN AF: 0.00614

Gnomad MID AF: 0.0159

Gnomad NFE AF: 0.0118

Gnomad OTH AF: 0.00764

GnomAD3 exomes AF: 0.0101 AC: 1437 AN: 142816 Hom.: 56 AF XY: 0.0108 AC XY: 832 AN XY: 76978

Gnomad AFR exome AF: 0.00210

Gnomad AMR exome AF: 0.00711

Gnomad ASJ exome AF: 0.0123

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00797

Gnomad FIN exome AF: 0.00675

Gnomad NFE exome AF: 0.0152

Gnomad OTH exome AF: 0.0176

GnomAD4 exome AF: 0.0110 AC: 14857 AN: 1355712 Hom.: 175 Cov.: 24 AF XY: 0.0108 AC XY: 7350 AN XY: 678004

Gnomad4 AFR exome AF: 0.00239

Gnomad4 AMR exome AF: 0.00549

Gnomad4 ASJ exome AF: 0.0108

Gnomad4 EAS exome AF: 0.0000254

Gnomad4 SAS exome AF: 0.00771

Gnomad4 FIN exome AF: 0.00677

Gnomad4 NFE exome AF: 0.0122

Gnomad4 OTH exome AF: 0.0121

GnomAD4 genome AF: 0.00747 AC: 1135 AN: 151862 Hom.: 5 Cov.: 32 AF XY: 0.00660 AC XY: 490 AN XY: 74234

Gnomad4 AFR AF: 0.00221

Gnomad4 AMR AF: 0.00517

Gnomad4 ASJ AF: 0.0124

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00726

Gnomad4 FIN AF: 0.00614

Gnomad4 NFE AF: 0.0118

Gnomad4 OTH AF: 0.00756

Alfa AF: 0.0113 Hom.: 13

Bravo AF: 0.00714

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Nov 03, 2020

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 17574468, 22008521, 22383692, 11571556) -

Dec 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PKD1: BP4, BP7, BS1, BS2 -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

-

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not specified Benign:1

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Polycystic kidney disease, adult type Benign:1

Feb 20, 2020

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Polycystic kidney disease Benign:1

-

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

The PKD1 p.Val3090Val variant was identified as a polymorphism in 8 of 804 proband chromosomes (frequency: 0.010) from individuals or families with ADPKD (Bataille 2011, Garcia-Gonzalez 2007, Rossetti 2012, Bouba 2001). The variant was also identified in dbSNP (ID: rs149056734) as “With unknown allele”, with a minor allele frequency of 0.0062 (31 of 5000 chromosomes in 1000 Genomes Project). The variant was identified in the NHLBI Exome Sequencing Project in 47 of 5946 European Americans and 4 of 2224 African American chromosomes. This variant was identified in the Exome Aggregation Consortium database (March 14, 2016) in 292 of 16060 chromosomes (frequency: 0.018 or 5 of 876 African , 19 of 508 Latino , 187 of 5858 European (Non-Finnish), 74 of 7872 South Asians, 5 of 90 Finnish and 2 of 156 other chromosomes and was not in found East Asian populations. The variant was identified in GeneInsight by one submitter and classified as benign. The variant was also identified in the PKD Mutation Database and classified as likely neutral. The p.Val3090Val 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 addition, this variant was identified in one individual from our laboratory as co-occurring with a pathogenic variant in PKD1 (c.7137C>G, p.Tyr2379X), increasing the likelihood this variant does not have clinical significance. In summary, based on the above information, this variant meets our laboratory criteria to be classified as benign. -

Autosomal dominant polycystic kidney disease Benign:1

Jan 01, 2019

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

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: research

- -

PKD1-related disorder Benign:1

Oct 31, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.52
CADD	Benign	1.1
DANN	Benign	0.45

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: rs149056734; hg19: chr16-2152189;