rs55840049

Variant names:

• chr16-2111116-G-A
• rs55840049
• NM_001009944.3:c.4051C>T

Your query was ambiguous. Multiple possible variants found:

• chr16-2111116-G-A
• chr16-2111116-G-C
• chr16-2111116-G-T

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.4051C>T​(p.Arg1351Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00096 in 1,610,818 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 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. R1351L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0047 (8 hom., cov: 33)
  • Exomes 𝑓: 0.00057 (5 hom.)
• Consequence: PKD1 NM_001009944.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:6
• Conservation: PhyloP100: 0.667
• Publications: 7 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=0.011341393).
• BP6: Variant 16-2111116-G-A is Benign according to our data. Variant chr16-2111116-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 225439.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00472 (719/152312) while in subpopulation AFR AF = 0.0163 (679/41570). AF 95% confidence interval is 0.0153. There are 8 homozygotes in GnomAd4. There are 348 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 8 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PKD1	NM_001009944.3	c.4051C>T	p.Arg1351Trp	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.4051C>T	p.Arg1351Trp	missense_variant	Exon 15 of 46	1	NM_001009944.3	ENSP00000262304.4

Frequencies

GnomAD3 genomes AF: 0.00472 AC: 719 AN: 152194 Hom.: 8 Cov.: 33

Gnomad AFR AF: 0.0164

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00150

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000964

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00383

GnomAD2 exomes AF: 0.00119 AC: 296 AN: 247814 AF XY: 0.000801

Gnomad AFR exome AF: 0.0148

Gnomad AMR exome AF: 0.000754

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00128

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000629

Gnomad OTH exome AF: 0.000496

GnomAD4 exome AF: 0.000567 AC: 827 AN: 1458506 Hom.: 5 Cov.: 36 AF XY: 0.000498 AC XY: 361 AN XY: 725606

African (AFR) AF: 0.0163 AC: 546 AN: 33416

American (AMR) AF: 0.000984 AC: 44 AN: 44702

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26110

East Asian (EAS) AF: 0.00300 AC: 119 AN: 39694

South Asian (SAS) AF: 0.0000696 AC: 6 AN: 86170

European-Finnish (FIN) AF: 0.0000384 AC: 2 AN: 52126

Middle Eastern (MID) AF: 0.00138 AC: 6 AN: 4350

European-Non Finnish (NFE) AF: 0.0000306 AC: 34 AN: 1111742

Other (OTH) AF: 0.00116 AC: 70 AN: 60196

GnomAD4 genome AF: 0.00472 AC: 719 AN: 152312 Hom.: 8 Cov.: 33 AF XY: 0.00467 AC XY: 348 AN XY: 74470

African (AFR) AF: 0.0163 AC: 679 AN: 41570

American (AMR) AF: 0.00150 AC: 23 AN: 15310

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

East Asian (EAS) AF: 0.000966 AC: 5 AN: 5174

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

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

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68022

Other (OTH) AF: 0.00379 AC: 8 AN: 2112

Alfa AF: 0.00165 Hom.: 0

Bravo AF: 0.00504

ESP6500AA AF: 0.0128 AC: 56

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00157 AC: 189

Asia WGS AF: 0.00202 AC: 7 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:6

Revision: criteria provided, conflicting classifications

Submissions by phenotype

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

Aug 22, 2023

Mendelics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 18, 2016

Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: reference population

- -

not specified Benign:2

Jul 30, 2024

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 01, 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.4051C>T (p.Arg1351Trp) results in a non-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 0.0012 in 248094 control chromosomes, predominantly at a frequency of 0.015 within the African or African-American subpopulation in the gnomAD database. The observed variant frequency within African or African-American 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.4051C>T has been observed in individual(s) affected with PKD1-related conditions without strong evidence for causality (Garcia-Gonzalez_2007, Kim_2019, Fujimaru_2018, Rossetti_2007), as well as healthy controls (Kinoshita_2016). 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 publications have been ascertained in the context of this evaluation (PMID: 29520754, 31740684, 27835667, 17582161, 17574468). ClinVar contains an entry for this variant (Variation ID: 225439). Based on the evidence outlined above, the variant was classified as likely benign. -

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.Arg1351Trp variant was identified in 2 of 568 proband chromosomes (frequency: 0.004) from individuals or families with ADPKD (Rossetti_2007, Garcia-Gonzalez_2007). The variant was also identified in dbSNP (ID: rs55840049) “With Uncertain significance allele”, ClinVar (classified uncertain significance by Soonchunhyang University Bucheon Hospital), ADPKD Mutation Database (classified likely neutral), and not in COGR, LOVD 3.0, and PKD1-LOVD. The variant was identified in control databases in 466 of 275234 chromosomes (2 homozygous) at a frequency of 0.002 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). It was observed in the following populations: African in 396 (1 homozygous) of 23852 chromosomes (freq: 0.02), Other in 7 of 6410 chromosomes (freq: 0.001), Latino in 28 of 34396 chromosomes (freq: 0.0008), European Non-Finnish in 10 of 125168 chromosomes (freq: 0.00008), East Asian in 23 (1 homozygous) of 18814 chromosomes (freq: 0.001), and South Asian in 2 of 30768 chromosomes (freq: 0.00007); it was not observed in the Ashkenazi Jewish and European Finnish populations. The p.Arg1351 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact of the variant Trp 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 in our laboratory in 1 individual with ADPKD, co-occurring with a pathogenic PKD1 variant (c.2494dupC, p.Arg832ProfsX40), increasing the likelihood it does not have clinical significance. In summary, based on the above information this variant meets our laboratory criteria to be classified as benign. -

not provided Benign:1

Feb 26, 2020

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 22995991, 17574468, 17582161) -

PKD1-related disorder Benign:1

Aug 20, 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
AlphaMissense	Benign	0.099
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.66	D;.
Eigen	Benign	-0.18
Eigen_PC	Benign	-0.39
FATHMM_MKL	Benign	0.11	N
LIST_S2	Uncertain	0.88	D;D
MetaRNN	Benign	0.011	T;T
MetaSVM	Benign	-0.80	T
MutationAssessor	Uncertain	2.3	M;M
PhyloP100		0.67
PrimateAI	Benign	0.23	T
PROVEAN	Uncertain	-2.8	D;D
REVEL	Benign	0.14
Sift	Uncertain	0.020	D;D
Sift4G	Uncertain	0.0030	D;D
Polyphen		1.0	D;D
Vest4		0.83
MVP		0.63
ClinPred		0.025	T
GERP RS		2.4
Varity_R		0.081
gMVP		0.58
Mutation Taster		=78/22	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: rs55840049; hg19: chr16-2161117;