chr16-2135583-G-T

Variant names:

• chr16-2135583-G-T
• rs560049593
• NM_001009944.3:c.107C>A

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001009944.3(PKD1):​c.107C>A​(p.Pro36His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0219 in 1,068,452 control chromosomes in the GnomAD database, including 292 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.016 (40 hom., cov: 31)
  • Exomes 𝑓: 0.023 (252 hom.)
• Consequence: PKD1 NM_001009944.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.708
• Publications: 10 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 -18 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 11 uncertain in NM_001009944.3
• BP4: Computational evidence support a benign effect (MetaRNN=0.010966539).
• BP6: Variant 16-2135583-G-T is Benign according to our data. Variant chr16-2135583-G-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 256895.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0165 (2436/147704) while in subpopulation NFE AF = 0.0227 (1505/66194). AF 95% confidence interval is 0.0218. There are 40 homozygotes in GnomAd4. There are 1217 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 40 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001009944.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PKD1	NM_001009944.3	MANE Select	c.107C>A	p.Pro36His	missense	Exon 1 of 46	NP_001009944.3
	PKD1	NM_000296.4		c.107C>A	p.Pro36His	missense	Exon 1 of 46	NP_000287.4

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PKD1	ENST00000262304.9	TSL:1 MANE Select	c.107C>A	p.Pro36His	missense	Exon 1 of 46	ENSP00000262304.4
	PKD1	ENST00000423118.5	TSL:1	c.107C>A	p.Pro36His	missense	Exon 1 of 46	ENSP00000399501.1

Frequencies

GnomAD3 genomes AF: 0.0165 AC: 2436 AN: 147602 Hom.: 40 Cov.: 31

Gnomad AFR AF: 0.00481

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0127

Gnomad ASJ AF: 0.0103

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00249

Gnomad FIN AF: 0.0527

Gnomad MID AF: 0.0160

Gnomad NFE AF: 0.0227

Gnomad OTH AF: 0.0113

GnomAD4 exome AF: 0.0228 AC: 20963 AN: 920748 Hom.: 252 Cov.: 28 AF XY: 0.0227 AC XY: 9785 AN XY: 430858

African (AFR) AF: 0.00287 AC: 51 AN: 17798

American (AMR) AF: 0.00891 AC: 31 AN: 3478

Ashkenazi Jewish (ASJ) AF: 0.0135 AC: 108 AN: 8022

East Asian (EAS) AF: 0.000188 AC: 2 AN: 10614

South Asian (SAS) AF: 0.00144 AC: 26 AN: 18022

European-Finnish (FIN) AF: 0.0464 AC: 423 AN: 9110

Middle Eastern (MID) AF: 0.00862 AC: 18 AN: 2088

European-Non Finnish (NFE) AF: 0.0241 AC: 19722 AN: 818894

Other (OTH) AF: 0.0178 AC: 582 AN: 32722

GnomAD4 genome AF: 0.0165 AC: 2436 AN: 147704 Hom.: 40 Cov.: 31 AF XY: 0.0169 AC XY: 1217 AN XY: 71970

African (AFR) AF: 0.00479 AC: 197 AN: 41110

American (AMR) AF: 0.0127 AC: 189 AN: 14874

Ashkenazi Jewish (ASJ) AF: 0.0103 AC: 35 AN: 3398

East Asian (EAS) AF: 0.00 AC: 0 AN: 5134

South Asian (SAS) AF: 0.00249 AC: 12 AN: 4822

European-Finnish (FIN) AF: 0.0527 AC: 470 AN: 8912

Middle Eastern (MID) AF: 0.0172 AC: 5 AN: 290

European-Non Finnish (NFE) AF: 0.0227 AC: 1505 AN: 66194

Other (OTH) AF: 0.0112 AC: 23 AN: 2060

Alfa AF: 0.00605 Hom.: 1

Bravo AF: 0.0137

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

May 02, 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.107C>A (p.Pro36His) 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 0.022 in 1068452 control chromosomes in the gnomAD database, including 292 homozygotes. The observed variant frequency exceeds the estimated maximal expected allele frequency for a pathogenic variant in PKD1 causing PKD1-Biallelic Autosomal Recessive Polycystic Kidney Disease phenotype. To our knowledge, no occurrence of c.107C>A in individuals affected with PKD1-Biallelic Autosomal Recessive Polycystic Kidney Disease and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 256895). Based on the evidence outlined above, the variant was classified as likely benign.

Feb 16, 2025

Laboratory of Genetics, Children's Clinical University Hospital Latvia

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Benign:2

Sep 25, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 22008521, 18640754)

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Polycystic kidney disease, adult type Benign:1

Feb 28, 2020

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

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: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

The PKD1 p.Pro36His variant was identified in 20 of 616 proband chromosomes (frequency: 0.03) from individuals or families with ADPKD (with or without family history), and was not identified in 150 control chromosomes from healthy individuals (Reed 2008, Bataille 2011, Peltola 2005, Rossetti 2012). Reed et al. could not classify the variant however the conservation score associated the variant with some evolutionary variability (Reed 2008). The variant was identified in dbSNP (ID: rs560049593) as “With other allele”, ClinVar (classified benign by ARUP, and likely benign by Prevention Genetics and GeneDx), and ADPKD Mutation Database (classified as likely neutral). The variant was not identified in PKD1-LOVD or LOVD 3.0. The variant was identified in control databases in 398 of 26042 chromosomes (3 homozygous) at a frequency of 0.02 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 44 of 8250 chromosomes (freq: 0.005), Other in 18 of 744 chromosomes (freq: 0.02), Latino in 2 of 396 chromosomes (freq: 0.005), European Non-Finnish in 266 of 13680 chromosomes (freq: 0.02), Ashkenazi Jewish in 1 of 224 chromosomes (freq: 0.004), European Finnish in 67 of 1126 chromosomes (freq: 0.06); it was not observed in the East Asian, and South Asian populations. The p.Pro36 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact of the variant His 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) do not predict a difference in splicing. In summary, based on the above information this variant meets our laboratory criteria to be classified as benign.

Autosomal dominant polycystic kidney disease Benign:1

Jan 01, 2019

Molecular Genetics of Inherited Kidney Disorders Laboratory, Garvan Institute of Medical Research

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: research

PKD1-related disorder Benign:1

Jul 23, 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 v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.26
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	21
DANN	Benign	0.83
DEOGEN2	Benign	0.18	T
Eigen	Benign	-0.36
Eigen_PC	Benign	-0.48
FATHMM_MKL	Benign	0.084	N
LIST_S2	Benign	0.45	T
M_CAP	Pathogenic	0.32	D
MetaRNN	Benign	0.011	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.34	N
PhyloP100		0.71
PrimateAI	Uncertain	0.78	T
PROVEAN	Benign	-0.65	N
REVEL	Benign	0.083
Sift	Benign	0.13	T
Sift4G	Pathogenic	0.0	D
Polyphen		0.99	D
Vest4		0.28
MVP		0.41
ClinPred		0.25	T
GERP RS		2.1
PromoterAI		0.016	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.3
Varity_R		0.11
gMVP		0.32
Mutation Taster		=92/8	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: rs560049593; hg19: chr16-2185584;