rs199476099

Positions:

• chr16-2118021-C-A
• chr16-2118021-C-T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 2P and 7B. PM1 BP4_Moderate BP6 BS2

The NM_001009944.3(PKD1):​c.971G>T​(p.Arg324Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0032 in 1,595,092 control chromosomes in the GnomAD database, including 22 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0034 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0032 (20 hom.)
• Consequence: PKD1 NM_001009944.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:2 B:7
• Conservation: PhyloP100: 0.0190

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 Likely_benign. Variant got -5 ACMG points.

• PM1: In a domain PKD 1 (size 87) in uniprot entity PKD1_HUMAN there are 10 pathogenic changes around while only 2 benign (83%) in NM_001009944.3
• BP4: Computational evidence support a benign effect (MetaRNN=0.08251116).
• BP6: Variant 16-2118021-C-A is Benign according to our data. Variant chr16-2118021-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 8205.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Benign=2, Uncertain_significance=1}. Variant chr16-2118021-C-A is described in Lovd as [Likely_benign].
• BS2: High AC in GnomAd4 at 512 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PKD1	NM_001009944.3	c.971G>T	p.Arg324Leu	missense_variant	5/46	ENST00000262304.9	NP_001009944.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PKD1	ENST00000262304.9	c.971G>T	p.Arg324Leu	missense_variant	5/46	1	NM_001009944.3	ENSP00000262304	P5
PKD1	ENST00000423118.5	c.971G>T	p.Arg324Leu	missense_variant	5/46	1		ENSP00000399501	A2
PKD1	ENST00000488185.2	c.59G>T	p.Arg20Leu	missense_variant	1/5	5		ENSP00000456672
PKD1	ENST00000570150.1	n.104G>T		non_coding_transcript_exon_variant	1/3	5

Frequencies

GnomAD3 genomes AF: 0.00337 AC: 513 AN: 152236 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00294

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00583

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00566

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.00250 AC: 476 AN: 190410 Hom.: 1 AF XY: 0.00243 AC XY: 256 AN XY: 105484

Gnomad AFR exome AF: 0.000287

Gnomad AMR exome AF: 0.000951

Gnomad ASJ exome AF: 0.00265

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000376

Gnomad FIN exome AF: 0.00551

Gnomad NFE exome AF: 0.00416

Gnomad OTH exome AF: 0.00298

GnomAD4 exome AF: 0.00318 AC: 4585 AN: 1442738 Hom.: 20 Cov.: 33 AF XY: 0.00323 AC XY: 2323 AN XY: 718328

Gnomad4 AFR exome AF: 0.000300

Gnomad4 AMR exome AF: 0.00135

Gnomad4 ASJ exome AF: 0.00230

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000151

Gnomad4 FIN exome AF: 0.00586

Gnomad4 NFE exome AF: 0.00367

Gnomad4 OTH exome AF: 0.00221

GnomAD4 genome AF: 0.00336 AC: 512 AN: 152354 Hom.: 2 Cov.: 32 AF XY: 0.00341 AC XY: 254 AN XY: 74502

Gnomad4 AFR AF: 0.000240

Gnomad4 AMR AF: 0.00294

Gnomad4 ASJ AF: 0.00144

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00583

Gnomad4 NFE AF: 0.00566

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.00419 Hom.: 1

Bravo AF: 0.00274

ESP6500AA AF: 0.000277 AC: 1

ESP6500EA AF: 0.00225 AC: 17

ExAC AF: 0.00225 AC: 261

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:2 Benign:7

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Polycystic kidney disease, adult type Pathogenic:1 Uncertain:2 Benign:1

Pathogenic, no assertion criteria provided	literature only	OMIM	Jul 01, 1999	- -
Uncertain significance, no assertion criteria provided	curation	Reproductive Health Research and Development, BGI Genomics	Jan 06, 2020	NM_001009944.2:c.971G>T in the PKD1 gene has an allele frequency of 0.006 in European (Finnish) subpopulation in the gnomAD database. This variant has been detected in a individual with autosomal dominant polycystic kidney disease (PMID: 10364515). Benign computational verdict because benign predictions from DEOGEN2, EIGEN, FATHMM-MKL, PrimateAI and SIFT. As a dominant inheritance manner, a total of 626 allleles was detected in gnomAD database which is a evidence to against its pathogenicity, although the adult-onset should be considered. We interpret it as variant of uncertain significance (VUS). ACMG/AMP criteria applied: PP4, BP4. -
Uncertain significance, criteria provided, single submitter	clinical testing	Centre for Mendelian Genomics, University Medical Centre Ljubljana	Jan 01, 2016	This variant was classified as: Uncertain significance. The following ACMG criteria were applied in classifying this variant: PS1,PP3,PP4,BP6,BS2. -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Apr 19, 2019	- -

not specified Benign:2

Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	Nov 03, 2022	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 24, 2023	Variant summary: PKD1 c.971G>T (p.Arg324Leu) results in a non-conservative amino acid change located in the PKD domain (IPR000601) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0025 in 190410 control chromosomes, predominantly at a frequency of 0.0042 within the Non-Finnish European subpopulation in the gnomAD database, including 1 homozygotes. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 8 fold of the estimated maximal expected allele frequency for a pathogenic variant in PKD1 causing Polycystic Kidney Disease 1 phenotype (0.0005), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. c.971G>T has been reported in the literature in individuals affected with Polycystic Kidney Disease however without strong evidence for segregation (examples: Thomas_1999, Carrera_2016, Mansilla_2021). At-least one of these reports classified the variant as benign (Carrera_ 2016). The following publications have been ascertained in the context of this evaluation (PMID: 31738409, 32512653, 10364515, 27499327, 19759016). Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after and classified the variant as benign/likely benign (n=3), uncertain significance (n=2) and likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as likely benign. -

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 15, 2020	This variant is associated with the following publications: (PMID: 10364515, 12662927, 27499327, 19759016, 21115670, 17582161) -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2024	PKD1: BP4, BS1, BS2 -

Polycystic kidney disease Benign:1

Benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The PKD1 p.Arg324Leu variant was identified in 6 of 720 proband chromosomes (frequency: 0.008) from individuals or families with ADPKD (Thomas 1999, Hoefele 2011, Rossetti 2007). The variant was also identified in dbSNP (ID: rs199476099) as “With Pathogenic allele”, Clinvitae (classified as pathogenic by ClinVar), ClinVar (classified as pathogenic by OMIM), MutDB, ADPKD Mutation Database (classified as likely neutral), and PKD1-LOVD 3.0 (probably does not affect function). This variant was identified in the 1000 Genomes Project in 5 of 5000 chromosomes (frequency: 0.001), the NHLBI GO Exome Sequencing Project in 17 of 7568 European American and in 1 of 3614 African American alleles, the genome Aggregation Database (beta, October 19th 2016) in 501 (1 homozygous) of 192856 chromosomes (freq. 0.003), the Exome Aggregation Consortium database (August 8th 2016) in 157 (1 homozygous) of 24970 chromosomes (freq. 0.006) in the following populations: European in 139 of 11896 chromosomes (freq. 0.01), Finnish in 9 of 402 chromosomes (freq. 0.02), Latino in 6 of 1292 chromosomes (freq. 0.004), African in 2 of 1452 chromosomes (freq. 0.001), Other in 1 of 204 chromosomes (freq. 0.005), increasing the likelihood this could be a low frequency benign variant. The p.Arg324 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of 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. In addition, the variant was identified with an unspecified co-occurring pathogenic variant increasing the likelihood that the p.Arg324Leu variant does not have clinical significance (Rossetti 2007). It was also identified in one individual from our lab in homozygous form, and with a co-occurring PKD2 pathogenic variant (c.1662G>A, p.Trp554X) increasing the likelihood that this variant does not have clinical significance. In summary, based on the above information, this variant is classified as benign. -

PKD1-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 14, 2020

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
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.14
CADD	Benign	17
DANN	Uncertain	0.99
DEOGEN2	Benign	0.29	T;.
Eigen	Benign	-0.47
Eigen_PC	Benign	-0.59
FATHMM_MKL	Benign	0.22	N
LIST_S2	Benign	0.80	T;T
MetaRNN	Benign	0.083	T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Uncertain	2.4	M;M
MutationTaster	Benign	0.00014	A;A
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-2.1	N;N
REVEL	Uncertain	0.36
Sift	Benign	0.067	T;T
Sift4G	Uncertain	0.033	D;D
Polyphen		0.87	P;B
Vest4		0.74
MVP		0.95
ClinPred		0.016	T
GERP RS		-0.52
Varity_R		0.25
gMVP		0.62

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: rs199476099; hg19: chr16-2168022;