rs2457533

Variant names:

• chr16-2106849-A-G
• rs2457533
• NM_001009944.3:c.7165T>C

Your query was ambiguous. Multiple possible variants found:

• chr16-2106849-A-G
• chr16-2106849-A-T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001009944.3(PKD1):​c.7165T>C​(p.Leu2389Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.113 in 1,378,590 control chromosomes in the GnomAD database, including 18,957 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.27 (7297 hom., cov: 30)
  • Exomes 𝑓: 0.094 (11660 hom.)
• Consequence: PKD1 NM_001009944.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 3.26
• Publications: 11 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]

MIR6511B1 (HGNC:50228): (microRNA 6511b-1) microRNAs (miRNAs) are short (20-24 nt) non-coding RNAs that are involved in post-transcriptional regulation of gene expression in multicellular organisms by affecting both the stability and translation of mRNAs. miRNAs are transcribed by RNA polymerase II as part of capped and polyadenylated primary transcripts (pri-miRNAs) that can be either protein-coding or non-coding. The primary transcript is cleaved by the Drosha ribonuclease III enzyme to produce an approximately 70-nt stem-loop precursor miRNA (pre-miRNA), which is further cleaved by the cytoplasmic Dicer ribonuclease to generate the mature miRNA and antisense miRNA star (miRNA*) products. The mature miRNA is incorporated into a RNA-induced silencing complex (RISC), which recognizes target mRNAs through imperfect base pairing with the miRNA and most commonly results in translational inhibition or destabilization of the target mRNA. The RefSeq represents the predicted microRNA stem-loop. [provided by RefSeq, Sep 2009]

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.61).
• BP6: Variant 16-2106849-A-G is Benign according to our data. Variant chr16-2106849-A-G is described in ClinVar as Benign. ClinVar VariationId is 256997.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=3.26 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.506 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PKD1	NM_001009944.3	c.7165T>C	p.Leu2389Leu	synonymous_variant	Exon 17 of 46	ENST00000262304.9	NP_001009944.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PKD1	ENST00000262304.9	c.7165T>C	p.Leu2389Leu	synonymous_variant	Exon 17 of 46	1	NM_001009944.3	ENSP00000262304.4

Frequencies

GnomAD3 genomes AF: 0.268 AC: 40243 AN: 150008 Hom.: 7270 Cov.: 30

Gnomad AFR AF: 0.511

Gnomad AMI AF: 0.127

Gnomad AMR AF: 0.192

Gnomad ASJ AF: 0.284

Gnomad EAS AF: 0.0317

Gnomad SAS AF: 0.125

Gnomad FIN AF: 0.239

Gnomad MID AF: 0.264

Gnomad NFE AF: 0.176

Gnomad OTH AF: 0.262

GnomAD2 exomes AF: 0.143 AC: 27649 AN: 192938 AF XY: 0.140

Gnomad AFR exome AF: 0.471

Gnomad AMR exome AF: 0.105

Gnomad ASJ exome AF: 0.248

Gnomad EAS exome AF: 0.0207

Gnomad FIN exome AF: 0.190

Gnomad NFE exome AF: 0.141

Gnomad OTH exome AF: 0.173

GnomAD4 exome AF: 0.0943 AC: 115809 AN: 1228468 Hom.: 11660 Cov.: 30 AF XY: 0.0944 AC XY: 58085 AN XY: 615468

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.397 AC: 8929 AN: 22482

American (AMR) AF: 0.0908 AC: 3787 AN: 41688

Ashkenazi Jewish (ASJ) AF: 0.214 AC: 4764 AN: 22306

East Asian (EAS) AF: 0.0347 AC: 1364 AN: 39334

South Asian (SAS) AF: 0.0891 AC: 7155 AN: 80260

European-Finnish (FIN) AF: 0.205 AC: 7307 AN: 35666

Middle Eastern (MID) AF: 0.186 AC: 651 AN: 3494

European-Non Finnish (NFE) AF: 0.0807 AC: 75125 AN: 930674

Other (OTH) AF: 0.128 AC: 6727 AN: 52564

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.269 AC: 40313 AN: 150122 Hom.: 7297 Cov.: 30 AF XY: 0.265 AC XY: 19432 AN XY: 73274

African (AFR) AF: 0.511 AC: 20562 AN: 40206

American (AMR) AF: 0.191 AC: 2904 AN: 15174

Ashkenazi Jewish (ASJ) AF: 0.284 AC: 977 AN: 3446

East Asian (EAS) AF: 0.0314 AC: 162 AN: 5156

South Asian (SAS) AF: 0.124 AC: 593 AN: 4780

European-Finnish (FIN) AF: 0.239 AC: 2500 AN: 10444

Middle Eastern (MID) AF: 0.271 AC: 79 AN: 292

European-Non Finnish (NFE) AF: 0.176 AC: 11882 AN: 67640

Other (OTH) AF: 0.259 AC: 540 AN: 2084

Alfa AF: 0.227 Hom.: 925

Bravo AF: 0.281

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 27, 2025

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

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Aug 29, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 22608885) -

Polycystic kidney disease, adult type Benign:1

Jul 07, 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 c.7165T>C , p.Leu2389Leu variant was identified in 18.75% of 8483 control alleles in the Exome Aggregation Consortium (March 14, 2016). According to ACMG guidelines for variant classification based on allele frequency, category BA1, this variant is considered benign and has not been further reviewed (Richards 2015). -

Autosomal dominant polycystic kidney disease Benign:1

Jan 01, 2019

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

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: research

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.61
CADD	Benign	7.7
DANN	Benign	0.43
PhyloP100		3.3
Mutation Taster		=100/0	polymorphism (auto)

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: rs2457533; hg19: chr16-2156850; COSMIC: COSV51921397; COSMIC: COSV51921397;