rs199476099

Variant names:

• chr16-2118021-C-A
• rs199476099
• NM_001009944.3:c.971G>T

Your query was ambiguous. Multiple possible variants found:

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

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_Moderate BP6 BS1 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. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R324C) has been classified as Uncertain significance.

• 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
• Publications: 20 publications found

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 Gene-Disease associations (from GenCC):

• autosomal dominant polycystic kidney disease

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• polycystic kidney disease 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Laboratory for Molecular Medicine, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• autosomal recessive polycystic kidney disease

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• Caroli disease

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp

ACMG classification

Our verdict: Benign. The variant received -11 ACMG points.

• 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 VariationId is 8205.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00336 (512/152354) while in subpopulation NFE AF = 0.00566 (385/68032). AF 95% confidence interval is 0.00519. There are 2 homozygotes in GnomAd4. There are 254 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PKD1	NM_001009944.3	c.971G>T	p.Arg324Leu	missense_variant	Exon 5 of 46	ENST00000262304.9	NP_001009944.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PKD1	ENST00000262304.9	c.971G>T	p.Arg324Leu	missense_variant	Exon 5 of 46	1	NM_001009944.3	ENSP00000262304.4

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

GnomAD2 exomes AF: 0.00250 AC: 476 AN: 190410 AF XY: 0.00243

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 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

African (AFR) AF: 0.000300 AC: 10 AN: 33284

American (AMR) AF: 0.00135 AC: 60 AN: 44446

Ashkenazi Jewish (ASJ) AF: 0.00230 AC: 60 AN: 26046

East Asian (EAS) AF: 0.00 AC: 0 AN: 39592

South Asian (SAS) AF: 0.000151 AC: 13 AN: 85834

European-Finnish (FIN) AF: 0.00586 AC: 247 AN: 42180

Middle Eastern (MID) AF: 0.000242 AC: 1 AN: 4124

European-Non Finnish (NFE) AF: 0.00367 AC: 4062 AN: 1107478

Other (OTH) AF: 0.00221 AC: 132 AN: 59754

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

African (AFR) AF: 0.000240 AC: 10 AN: 41580

American (AMR) AF: 0.00294 AC: 45 AN: 15312

Ashkenazi Jewish (ASJ) AF: 0.00144 AC: 5 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5174

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00583 AC: 62 AN: 10630

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00566 AC: 385 AN: 68032

Other (OTH) AF: 0.00189 AC: 4 AN: 2116

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

Apr 19, 2019

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 01, 1999

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Jan 01, 2016

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was classified as: Uncertain significance. The following ACMG criteria were applied in classifying this variant: PS1,PP3,PP4,BP6,BS2. -

Jan 06, 2020

Reproductive Health Research and Development, BGI Genomics

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: curation

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. -

not specified Benign:2

Jun 16, 2025

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change. 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 exceeds the estimated maximal expected allele frequency for a pathogenic variant in PKD1 causing PKD1-Biallelic Autosomal Recessive Polycystic Kidney Disease phenotype. c.971G>T has been observed in individual(s) affected with PKD1-Biallelic Autosomal Recessive Polycystic Kidney Disease. These report(s) do not provide unequivocal conclusions about association of the variant with PKD1-Biallelic Autosomal Recessive Polycystic Kidney Disease. One publication reports experimental evidence evaluating an impact on protein function, however, does not allow convincing conclusions about the variant effect. ClinVar contains an entry for this variant (Variation ID: 8205). Based on the evidence outlined above, the variant was classified as likely benign. -

Nov 03, 2022

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided Benign:2

Jun 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PKD1: BP4, BS1, BS2 -

Sep 15, 2020

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 10364515, 12662927, 27499327, 19759016, 21115670, 17582161) -

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.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

Sep 14, 2020

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
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
PhyloP100		0.019
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
PromoterAI		-0.020	Neutral
Varity_R		0.25
gMVP		0.62
Mutation Taster		=79/21	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs199476099; hg19: chr16-2168022;