rs147788838

Variant names:

• chr16-2103344-C-T
• rs147788838
• NM_001009944.3:c.8713G>A

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001009944.3(PKD1):​c.8713G>A​(p.Val2905Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00311 in 1,605,844 control chromosomes in the GnomAD database, including 20 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 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 0.0018 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0032 (18 hom.)
• Consequence: PKD1 NM_001009944.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:8
• Conservation: PhyloP100: 2.37
• Publications: 6 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.013485014).
• BP6: Variant 16-2103344-C-T is Benign according to our data. Variant chr16-2103344-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 257028.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00179 (273/152284) while in subpopulation NFE AF = 0.00288 (196/68020). AF 95% confidence interval is 0.00255. There are 2 homozygotes in GnomAd4. There are 121 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.8713G>A	p.Val2905Ile	missense_variant	Exon 23 of 46	ENST00000262304.9	NP_001009944.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PKD1	ENST00000262304.9	c.8713G>A	p.Val2905Ile	missense_variant	Exon 23 of 46	1	NM_001009944.3	ENSP00000262304.4

Frequencies

GnomAD3 genomes AF: 0.00179 AC: 273 AN: 152166 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000941

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00137

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.000754

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00288

Gnomad OTH AF: 0.00335

GnomAD2 exomes AF: 0.00170 AC: 407 AN: 238784 AF XY: 0.00169

Gnomad AFR exome AF: 0.000907

Gnomad AMR exome AF: 0.00195

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000409

Gnomad NFE exome AF: 0.00277

Gnomad OTH exome AF: 0.00253

GnomAD4 exome AF: 0.00324 AC: 4714 AN: 1453560 Hom.: 18 Cov.: 34 AF XY: 0.00312 AC XY: 2259 AN XY: 723358

African (AFR) AF: 0.000928 AC: 31 AN: 33398

American (AMR) AF: 0.00181 AC: 81 AN: 44698

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26108

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39694

South Asian (SAS) AF: 0.0000929 AC: 8 AN: 86154

European-Finnish (FIN) AF: 0.000483 AC: 23 AN: 47658

Middle Eastern (MID) AF: 0.000242 AC: 1 AN: 4136

European-Non Finnish (NFE) AF: 0.00393 AC: 4364 AN: 1111574

Other (OTH) AF: 0.00339 AC: 204 AN: 60140

GnomAD4 genome AF: 0.00179 AC: 273 AN: 152284 Hom.: 2 Cov.: 32 AF XY: 0.00163 AC XY: 121 AN XY: 74460

African (AFR) AF: 0.000938 AC: 39 AN: 41556

American (AMR) AF: 0.00137 AC: 21 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4830

European-Finnish (FIN) AF: 0.000754 AC: 8 AN: 10616

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

European-Non Finnish (NFE) AF: 0.00288 AC: 196 AN: 68020

Other (OTH) AF: 0.00331 AC: 7 AN: 2112

Alfa AF: 0.00273 Hom.: 0

Bravo AF: 0.00193

ESP6500AA AF: 0.000952 AC: 4

ESP6500EA AF: 0.00265 AC: 22

ExAC AF: 0.00147 AC: 175

EpiCase AF: 0.00382

EpiControl AF: 0.00320

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:8

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:5

Jan 25, 2019

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Nov 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PKD1: BP4, BS2

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

not specified Benign:2

Jun 04, 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.8713G>A (p.Val2905Ile) results in a conservative amino acid change in 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 0.0017 in 238784 control chromosomes, predominantly at a frequency of 0.0028 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.8713G>A has been observed in individual(s) affected with PKD1-Biallelic Autosomal Recessive Polycystic Kidney Disease, however a pathogenic variant was identified in the patient (Zacchla_2021). These report(s) do not provide unequivocal conclusions about association of the variant with PKD1-Biallelic Autosomal Recessive Polycystic Kidney Disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 33964006). ClinVar contains an entry for this variant (Variation ID: 257028). Based on the evidence outlined above, the variant was classified as likely benign.

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Polycystic kidney disease, adult type Uncertain:1

Feb 26, 2020

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The PKD1 c.8713G>A; p.Val2905Ile variant (rs147788838) is reported in the literature as a benign polymorphism (Rossetti 2001). This variant is also reported in ClinVar (Variation ID: 257028), and is found in the general population with an overall allele frequency of 0.17% (457/270176 alleles, including a single homozygote) in the Genome Aggregation Database. The valine at codon 2905 is highly conserved, but computational analyses (SIFT, PolyPhen-2) predict that this variant is tolerated. However, given the lack of clinical and functional data, the significance of the p.Val2905Ile variant is uncertain at this time. References: Rossetti S et al. Mutation analysis of the entire PKD1 gene: genetic and diagnostic implications. Am J Hum Genet. 2001 Jan;68(1):46-63.

Polycystic kidney disease Benign:1

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

The PKD1 p.Val2905Ile variant was identified as a polymorphism in the literature in a cohort of 131 patients with ADPKD however frequency information was not reported (Rossetti 2001). The variant was also identified in dbSNP (ID: rs147788838) as “NA”, and the ADPKD Mutation Database (classification “likely neutral”) but not in Clinvitae, ClinVar, GeneInsight COGR, PKD1-LOVD, or PKD1-LOVD 3.0 databases. The variant was identified in the 1000 Genomes Project in 7 of 5000 chromosomes (frequency: 0.0014); HAPMAP populations: AMR in 1 of 694 chromosomes (frequency: 0.0014), EUR in 5 of 1006 chromosomes (frequency: 0.005), and AFR in 1 of 1322 chromosomes (frequency: 0.0008); the NHLBI GO Exome Sequencing Project in 22 of 8316 European American alleles and in 4 of 4202 African American alleles; and in the Exome Aggregation Consortium database (March 14, 2016): 30 of 11356 alleles (frequency: 0.0026) in a Latino population, in 129 of 61572 alleles (1 homozygous, frequency: 0.0021) from a European (Non-Finnish) population, in 1 of 8386 alleles (frequency: 0.0001) from a East Asian population, in 6 of 8310 alleles (frequency: 0.0007) from an African population, in 3 of 16374 alleles (frequency: 0.0002) from a population of South Asian and in 2 of 6556 alleles (frequency: 0.0003) from a population of European (Finnish) individuals; it was not seen in “Other” population. The p.Val2905 residue is not conserved in mammals and the variant amino acid Ile is present in dog, increasing the likelihood that this variant does not have clinical significance. 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. This variant was identified in our laboratory in one individual with ADPKD and a co-occurring pathogenic variant in PKD1 (c.160_166dup, p.Leu56ProfsX60), increasing the likelihood this variant does not have clinical significance. In summary, based on the above information this variant is classified as likely benign.

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	17
DANN	Benign	0.86
DEOGEN2	Benign	0.20	T;.
Eigen	Benign	-0.28
Eigen_PC	Benign	-0.28
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Benign	0.68	T;T
M_CAP	Uncertain	0.25	D
MetaRNN	Benign	0.013	T;T
MetaSVM	Benign	-0.75	T
MutationAssessor	Benign	1.9	L;L
PhyloP100		2.4
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-0.39	N;N
REVEL	Benign	0.098
Sift	Benign	0.14	T;T
Sift4G	Benign	0.13	T;T
Vest4		0.34
ClinPred		0.0088	T
GERP RS		4.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.023
gMVP		0.36
Mutation Taster		=94/6	polymorphism

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: rs147788838; hg19: chr16-2153345;