16-2112358-G-A

Variant names:

• chr16-2112358-G-A
• rs146352591
• NM_001009944.3:c.3277C>T

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 2P and 13B. PM1 BP4_Strong BP6 BS1 BS2

The NM_001009944.3(PKD1):​c.3277C>T​(p.His1093Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.000763 in 1,587,338 control chromosomes in the GnomAD database, including 9 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. H1093D) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0047 (6 hom., cov: 33)
  • Exomes 𝑓: 0.00035 (3 hom.)
• Consequence: PKD1 NM_001009944.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:5
• Conservation: PhyloP100: 4.32
• 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

ENSG00000261240 (HGNC:):

ACMG classification

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

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 benign, 9 uncertain in NM_001009944.3
• BP4: Computational evidence support a benign effect (MetaRNN=0.008589417).
• BP6: Variant 16-2112358-G-A is Benign according to our data. Variant chr16-2112358-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 447978.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00469 (714/152362) while in subpopulation AFR AF = 0.0162 (672/41578). AF 95% confidence interval is 0.0152. There are 6 homozygotes in GnomAd4. There are 332 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 6 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PKD1	NM_001009944.3	c.3277C>T	p.His1093Tyr	missense_variant	Exon 14 of 46	ENST00000262304.9	NP_001009944.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PKD1	ENST00000262304.9	c.3277C>T	p.His1093Tyr	missense_variant	Exon 14 of 46	1	NM_001009944.3	ENSP00000262304.4

Frequencies

GnomAD3 genomes AF: 0.00468 AC: 712 AN: 152244 Hom.: 6 Cov.: 33

Gnomad AFR AF: 0.0162

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00382

GnomAD2 exomes AF: 0.000743 AC: 166 AN: 223404 AF XY: 0.000550

Gnomad AFR exome AF: 0.0109

Gnomad AMR exome AF: 0.000830

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000192

Gnomad OTH exome AF: 0.000524

GnomAD4 exome AF: 0.000346 AC: 497 AN: 1434976 Hom.: 3 Cov.: 32 AF XY: 0.000298 AC XY: 213 AN XY: 714098

African (AFR) AF: 0.0120 AC: 379 AN: 31552

American (AMR) AF: 0.000926 AC: 41 AN: 44296

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25926

East Asian (EAS) AF: 0.00 AC: 0 AN: 39660

South Asian (SAS) AF: 0.0000701 AC: 6 AN: 85574

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 37632

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4108

European-Non Finnish (NFE) AF: 0.0000181 AC: 20 AN: 1106524

Other (OTH) AF: 0.000854 AC: 51 AN: 59704

GnomAD4 genome AF: 0.00469 AC: 714 AN: 152362 Hom.: 6 Cov.: 33 AF XY: 0.00446 AC XY: 332 AN XY: 74504

African (AFR) AF: 0.0162 AC: 672 AN: 41578

American (AMR) AF: 0.00196 AC: 30 AN: 15308

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

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

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 68038

Other (OTH) AF: 0.00378 AC: 8 AN: 2116

Alfa AF: 0.00185 Hom.: 0

Bravo AF: 0.00565

ExAC AF: 0.000811 AC: 93

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1 Benign:1

Jun 19, 2025

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

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: PKD1 c.3277C>T (p.His1093Tyr) 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 0.00074 in 223404 control chromosomes in the gnomAD database, including 1 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.3277C>T has been observed in a family from autosomal dominant polycystic kidney disease (ADPKD) cohort study without strong evidence for causality (Rossetti_2007). These report(s) do not provide unequivocal conclusions about association of the variant with PKD1-Biallelic Autosomal Recessive Polycystic Kidney Disease. The following publications have been ascertained in the context of this evaluation (PMID: 17582161, 26139440). ClinVar contains an entry for this variant (Variation ID: 447978). Based on the evidence outlined above, the variant was classified as uncertain significance. -

May 25, 2017

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:2

Sep 17, 2020

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Polycystic kidney disease, adult type Benign:1

Nov 21, 2019

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.His1093Tyr variant was identified in 1 of 404 proband chromosomes (frequency: 0.002) from individuals or families with ADPKD (Rossetti_2007_17582161). The variant was also identified in dbSNP (ID: rs146352591) as “NA”, ClinVar (classified benign by Athena Diagnostics Inc), ADPKD Mutation Database (classified likely neutral). The variant was not identified in GeneInsight-COGR, LOVD 3.0, PKD1-LOVD databases. The variant was identified in control databases in 314 of 250392 chromosomes (1 homozygous) at a frequency of 0.001 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). Breakdown of the observations by population include African in 278 (1 homozygous) of 19826 chromosomes (freq: 0.01), Other in 2 of 6066 chromosomes (freq: 0.0003), Latino in 27 of 33734 chromosomes (freq: 0.0008), European Non-Finnish in 4 of 118028 chromosomes (freq: 0.00003), and South Asian in 3 of 29860 chromosomes (freq: 0.0001) while not observed in the Ashkenazi Jewish, East Asian and European Finnish populations. 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 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. The p.His1093 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact of the variant Tyr 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 summary, based on the above information this variant meets our laboratory criteria to be classified as benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Uncertain	-0.010
CADD	Benign	21
DANN	Benign	0.92
DEOGEN2	Benign	0.25	T;.
Eigen	Uncertain	0.23
Eigen_PC	Benign	0.15
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.77	T;T
MetaRNN	Benign	0.0086	T;T
MetaSVM	Uncertain	-0.17	T
MutationAssessor	Benign	1.8	L;L
PhyloP100		4.3
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	-1.1	N;N
REVEL	Uncertain	0.43
Sift	Benign	0.56	T;T
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;D
Vest4		0.74
MVP		0.95
ClinPred		0.036	T
GERP RS		5.3
PromoterAI		0.022	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.053
gMVP		0.74
Mutation Taster		=92/8	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs146352591; hg19: chr16-2162359;