rs139971481

Variant names:

• chr16-2108418-G-A
• rs139971481
• NM_001009944.3:c.6749C>T

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_Moderate BS1_Supporting BS2

The NM_001009944.3(PKD1):​c.6749C>T​(p.Thr2250Met) variant causes a missense change. The variant allele was found at a frequency of 0.00325 in 1,610,544 control chromosomes in the GnomAD database, including 16 homozygotes. In-silico tool predicts 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. T2250S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0022 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0034 (16 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: 4.05
• Publications: 12 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 -7 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.18780598).
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00217 (330/152336) while in subpopulation AMR AF = 0.00464 (71/15312). AF 95% confidence interval is 0.00377. There are 0 homozygotes in GnomAd4. There are 143 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAdExome4 at 16 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PKD1	NM_001009944.3	c.6749C>T	p.Thr2250Met	missense_variant	Exon 15 of 46	ENST00000262304.9	NP_001009944.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PKD1	ENST00000262304.9	c.6749C>T	p.Thr2250Met	missense_variant	Exon 15 of 46	1	NM_001009944.3	ENSP00000262304.4

Frequencies

GnomAD3 genomes AF: 0.00217 AC: 330 AN: 152218 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000700

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00464

Gnomad ASJ AF: 0.00288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00103

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00303

Gnomad OTH AF: 0.00287

GnomAD2 exomes AF: 0.00232 AC: 576 AN: 248540 AF XY: 0.00243

Gnomad AFR exome AF: 0.000436

Gnomad AMR exome AF: 0.00267

Gnomad ASJ exome AF: 0.00170

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000232

Gnomad NFE exome AF: 0.00357

Gnomad OTH exome AF: 0.00165

GnomAD4 exome AF: 0.00337 AC: 4909 AN: 1458208 Hom.: 16 Cov.: 33 AF XY: 0.00329 AC XY: 2388 AN XY: 725404

African (AFR) AF: 0.000569 AC: 19 AN: 33404

American (AMR) AF: 0.00295 AC: 132 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.00172 AC: 45 AN: 26124

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39696

South Asian (SAS) AF: 0.00157 AC: 135 AN: 86162

European-Finnish (FIN) AF: 0.000192 AC: 10 AN: 52094

Middle Eastern (MID) AF: 0.00121 AC: 5 AN: 4136

European-Non Finnish (NFE) AF: 0.00395 AC: 4390 AN: 1111704

Other (OTH) AF: 0.00286 AC: 172 AN: 60180

GnomAD4 genome AF: 0.00217 AC: 330 AN: 152336 Hom.: 0 Cov.: 33 AF XY: 0.00192 AC XY: 143 AN XY: 74486

African (AFR) AF: 0.000697 AC: 29 AN: 41580

American (AMR) AF: 0.00464 AC: 71 AN: 15312

Ashkenazi Jewish (ASJ) AF: 0.00288 AC: 10 AN: 3470

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

South Asian (SAS) AF: 0.00103 AC: 5 AN: 4834

European-Finnish (FIN) AF: 0.000188 AC: 2 AN: 10626

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00303 AC: 206 AN: 68022

Other (OTH) AF: 0.00284 AC: 6 AN: 2114

Alfa AF: 0.00261 Hom.: 0

Bravo AF: 0.00274

ESP6500AA AF: 0.000684 AC: 3

ESP6500EA AF: 0.00280 AC: 24

ExAC AF: 0.00217 AC: 262

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.00387

EpiControl AF: 0.00492

ClinVar

Significance: Conflicting classifications of pathogenicity

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

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:4

-

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

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

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

- -

Apr 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PKD1: BS1, BS2 -

-

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

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

May 28, 2019

Mendelics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 21, 2019

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The PKD1 c.6749C>T, p.Thr2250Met variant (rs139971481) has been reported in individuals diagnosed with ADPKD (Irazabal 2011, Perrichot 2000, Reiterova 2013, Rossetti 2012) but has also been found to co-occur with truncating PKD1 variants (Mayo ADPKD database). In one individual, the p.Thr2250Met variant was found in-trans with a truncating PKD1 variant and correlated with a more severe polycystic disorder, suggesting a possible modifier effect (Reiterova 2013). Individuals heterozygous for this variant exhibit either a mild cystic disease or no clinical phenotypes (Kleffman 2012, Reiterova 2013). This variant is found in the non-Finnish European population with an overall allele frequency of 0.35% (444/127104 alleles, including three homozygotes) in the Genome Aggregation Database. The threonine at codon 2250 is moderately conserved and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Although the population frequency and clinical phenotypes suggest that the p.Thr2250Met may not be a causative variant on its own, its potential effect as a disease modifier cannot be excluded. Thus, the clinical significance of p.Thr2250Met cannot be determined with certainty. References: Mayo ADPKD database: http://pkdb.mayo.edu/ Irazabal M et al. Extended follow-up of unruptured intracranial aneurysms detected by presymptomatic screening in patients with autosomal dominant polycystic kidney disease. Clin J Am Soc Nephrol. 2011 Jun;6(6):1274-85. Kleffman J et al. Dosage-sensitive network in polycystic kidney and liver disease: multiple mutations cause severe hepatic and neurological complications. J Hepatol. 2012 Aug;57(2):476-7. Perrichot R et al. Novel mutations in the duplicated region of PKD1 gene. Eur J Hum Genet. 2000 May;8(5):353-9. Reiterova J et al. Autosomal dominant polycystic kidney disease in a family with mosaicism and hypomorphic allele. BMC Nephrol. 2013 Mar 15;14:59. -

PKD1-Biallelic Autosomal Recessive Polycystic Kidney Disease Pathogenic:1

Apr 22, 2025

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: PKD1 c.6749C>T (p.Thr2250Met) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0023 in 248540 control chromosomes in the gnomAD database, including 4 homozygotes. This frequency is not significantly higher than estimated for a pathogenic variant in PKD1 causing PKD1-Biallelic Autosomal Recessive Polycystic Kidney Disease, allowing no conclusion about variant significance. c.6749C>T has been reported in the literature in individuals affected with PKD1-Biallelic Autosomal Recessive Polycystic Kidney Disease (e.g. Reiterova_2013, Paul_2014, Mantovani_2020, Gulati_2023). These individuals were compound heterozygous with either pathogenic truncating variants or another putative hypomorphic variant, and some family members who carried the variant had mild cystic kidney disease. These data indicate that the variant is likely to be associated with disease as a hypomorphic allele. The following publications have been ascertained in the context of this evaluation (PMID: 36706243, 23496908, 23496908, 21551026, 32457805, 23760289, 27499327, 22406737, 22383692, 26489027, 35368817, 24162162). ClinVar contains an entry for this variant (Variation ID: 447996). Based on the evidence supporting a hypomorphic effect as outlined above, this variant was classified as pathogenic for PKD1-Biallelic Autosomal Recessive Polycystic Kidney Disease. -

PKD1-related disorder Uncertain:1

Aug 06, 2024

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The PKD1 c.6749C>T variant is predicted to result in the amino acid substitution p.Thr2250Met. This variant has been suggested to be a hypomorphic allele for autosomal dominant polycystic kidney disease (ADPKD) (Reiterová et al. 2013. PubMed ID: 23496908; Irazabal et al. 2011. PubMed ID: 21551026; Perrichot et al. 2000. PubMed ID: 10854095). This type of variant alone in PKD1 probably does not cause ADPKD, but it may act as a hypomorphic allele or modifier to contribute to the disease severity when present in trans with a typical pathogenic or milder PKD1 variant. This variant is reported in 0.35% of alleles (with three homozygotes) in individuals of European (Non-Finnish) descent in gnomAD. Although we suspect that this variant may be benign due to its relatively high minor allele frequency in the general population, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

not specified Benign:1

Mar 24, 2017

Athena Diagnostics

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: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

The PKD1 p.Thr2250Met variant was identified in 9 of 932 proband chromosomes (frequency: 0.01) from individuals or families with ADPKD (Irazabal 2011, Paul 2014, Perrichot 2000, Rossetti 2012). The variant was also identified in dbSNP (ID: rs139971481) as “N/A”, the ADPKD Mutation Database (classified as likely neutral) and PKD1-LOVD 3.0 (classified as unknown effect). This variant was identified in the 1000 Genomes Project in 7 of 5000 chromosomes (frequency: 0.001), the NHLBI GO Exome Sequencing Project in 24 of 8584 European American and in 3 of 4388 African American alleles, the Exome Aggregation Consortium database (August 8th 2016) in 262 (4 homozygous) of 119152 chromosomes (freq. 0.002) in the following populations: European in 204 of 64980 chromosomes (freq. 0.003), Latino in 26 of 11528 chromosomes (freq. 0.002), Asian in 26 of 16500 chromosomes (freq. 0.002), African in 3 of 10108 chromosomes (freq. 0.0003), Finnish in 2 of 6588 chromosomes (freq. 0.0003) and Other in 1 of 880 chromosomes (freq. 0.001), increasing the likelihood this could be a low frequency benign variant. 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 p.Thr2250 residue is 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 2 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In two different case studies suggest the variant has a dosage effect and is most likely an incompletely penetrant allele (Kleffmann 2012, Reiterova 2013). However in the Kleffman study they report a 39 year old female homozygous for the p.The2250Met variant who does not have kidney cysts, suggesting that this variant may not cause typical polycystic kidney disease. This variant located in the REJ domain of PC-1 and cleavage of PC-1 at the GPS site can be affected by variants in this domain, however, analysis by Paul (2014) did not show that p.Thr2250Met variant influences this cleavage. 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Uncertain	0.060
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.43	T;.
Eigen	Uncertain	0.55
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.90	D;D
M_CAP	Pathogenic	0.93	D
MetaRNN	Benign	0.19	T;T
MetaSVM	Uncertain	0.11	D
MutationAssessor	Uncertain	2.6	M;M
PhyloP100		4.0
PrimateAI	Uncertain	0.62	T
PROVEAN	Uncertain	-3.0	D;D
REVEL	Uncertain	0.58
Sift	Uncertain	0.0030	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;D
Vest4		0.90
MVP		0.90
ClinPred		0.012	T
GERP RS		5.3
Varity_R		0.20
gMVP		0.56
Mutation Taster		=45/55	disease causing

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: rs139971481; hg19: chr16-2158419;