chr16-2112452-C-T

Variant names:

• chr16-2112452-C-T
• rs148727945
• NM_001009944.3:c.3183G>A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001009944.3(PKD1):​c.3183G>A​(p.Glu1061Glu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0027 in 1,588,386 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0016 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0028 (12 hom.)
• Consequence: PKD1 NM_001009944.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -0.407
• Publications: 0 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.76).
• BP6: Variant 16-2112452-C-T is Benign according to our data. Variant chr16-2112452-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 256945.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.407 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0016 (244/152322) while in subpopulation NFE AF = 0.00268 (182/68012). AF 95% confidence interval is 0.00236. There are 1 homozygotes in GnomAd4. There are 109 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 12 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PKD1	NM_001009944.3	c.3183G>A	p.Glu1061Glu	synonymous_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.3183G>A	p.Glu1061Glu	synonymous_variant	Exon 14 of 46	1	NM_001009944.3	ENSP00000262304.4

Frequencies

GnomAD3 genomes AF: 0.00160 AC: 244 AN: 152204 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000676

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00111

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000753

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00268

Gnomad OTH AF: 0.00382

GnomAD2 exomes AF: 0.00153 AC: 291 AN: 190260 AF XY: 0.00152

Gnomad AFR exome AF: 0.000403

Gnomad AMR exome AF: 0.00159

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00263

Gnomad OTH exome AF: 0.00236

GnomAD4 exome AF: 0.00282 AC: 4048 AN: 1436064 Hom.: 12 Cov.: 32 AF XY: 0.00268 AC XY: 1911 AN XY: 714122

African (AFR) AF: 0.000603 AC: 20 AN: 33180

American (AMR) AF: 0.00146 AC: 64 AN: 43794

Ashkenazi Jewish (ASJ) AF: 0.0000386 AC: 1 AN: 25914

East Asian (EAS) AF: 0.000101 AC: 4 AN: 39530

South Asian (SAS) AF: 0.0000235 AC: 2 AN: 85000

European-Finnish (FIN) AF: 0.000430 AC: 16 AN: 37218

Middle Eastern (MID) AF: 0.000243 AC: 1 AN: 4116

European-Non Finnish (NFE) AF: 0.00339 AC: 3760 AN: 1107590

Other (OTH) AF: 0.00301 AC: 180 AN: 59722

GnomAD4 genome AF: 0.00160 AC: 244 AN: 152322 Hom.: 1 Cov.: 33 AF XY: 0.00146 AC XY: 109 AN XY: 74484

African (AFR) AF: 0.000674 AC: 28 AN: 41572

American (AMR) AF: 0.00111 AC: 17 AN: 15306

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

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.000753 AC: 8 AN: 10618

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

European-Non Finnish (NFE) AF: 0.00268 AC: 182 AN: 68012

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

Alfa AF: 0.00226 Hom.: 0

Bravo AF: 0.00167

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:5

-

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

- -

Nov 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PKD1: BP4, BP7, BS2 -

Jan 24, 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

- -

Oct 22, 2020

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:2

Apr 25, 2025

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

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Polycystic kidney disease, adult type Benign:2

Jul 23, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 26, 2020

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Likely 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.Glu1061Glu variant was identified in 1 of 164 proband chromosomes (frequency: 0.006) from individuals or families with clinical features of polycystic renal disease (Garcia-Gonzalez 2007). The variant was also identified in dbSNP (ID: rs148727945) as “NA”, in the ADPKD Mutation Database (classification “likely neutral”), but was not in Clinvitae, ClinVar , GeneInsight COGR, PKD1-LOVD, and PKD1-LOVD 3.0. This variant was identified in the 1000 Genomes Project in 5 of 5000 chromosomes (frequency: 0.001), HAPMAP-EUR in 5 of 1006 chromosomes (frequency: 0.005), NHLBI GO Exome Sequencing Project in 10 of 4570 European American alleles and in 2 of 2590 African American alleles, and in the Exome Aggregation Consortium database (March 14, 2016) in 84 of 43768 alleles, specifically in 68 of 22746 alleles (1 homozygous, frequency: 0.0030) from a population of European (Non-Finnish) individuals, in 14 of 3386 alleles (frequency: 0.0041) from a Latino population, and in 2 of 2432 alleles (frequency: 0.0008) from an African population. The variant was not seen in East Asian, South Asian, or European (Finnish) populations. The p.Glu1061Glu variant is not expected to have clinical significance because it does not result in a change of amino acid and is not located in a known consensus splice site. In addition, in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. 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 meets our laboratory criteria to be classified as benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
CADD	Benign	4.9
DANN	Benign	0.74
PhyloP100		-0.41
PromoterAI		0.0085	Neutral
Mutation Taster		=100/0	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: rs148727945; hg19: chr16-2162453;