rs11643513

Variant names:

• chr16-2117969-G-A
• rs11643513
• NM_001009944.3:c.1023C>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.1023C>T​(p.Ala341Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0432 in 1,538,560 control chromosomes in the GnomAD database, including 1,555 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.038 (178 hom., cov: 32)
  • Exomes 𝑓: 0.044 (1377 hom.)
• Consequence: PKD1 NM_001009944.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -1.11
• 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

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 16-2117969-G-A is Benign according to our data. Variant chr16-2117969-G-A is described in ClinVar as Benign. ClinVar VariationId is 256887.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.11 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0812 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PKD1	NM_001009944.3	c.1023C>T	p.Ala341Ala	synonymous_variant	Exon 5 of 46	ENST00000262304.9	NP_001009944.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PKD1	ENST00000262304.9	c.1023C>T	p.Ala341Ala	synonymous_variant	Exon 5 of 46	1	NM_001009944.3	ENSP00000262304.4

Frequencies

GnomAD3 genomes AF: 0.0385 AC: 5860 AN: 152132 Hom.: 179 Cov.: 32

Gnomad AFR AF: 0.00898

Gnomad AMI AF: 0.0154

Gnomad AMR AF: 0.0852

Gnomad ASJ AF: 0.0242

Gnomad EAS AF: 0.000580

Gnomad SAS AF: 0.0128

Gnomad FIN AF: 0.0522

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.0498

Gnomad OTH AF: 0.0353

GnomAD2 exomes AF: 0.0493 AC: 6493 AN: 131760 AF XY: 0.0438

Gnomad AFR exome AF: 0.00891

Gnomad AMR exome AF: 0.124

Gnomad ASJ exome AF: 0.0247

Gnomad EAS exome AF: 0.000285

Gnomad FIN exome AF: 0.0577

Gnomad NFE exome AF: 0.0467

Gnomad OTH exome AF: 0.0477

GnomAD4 exome AF: 0.0437 AC: 60616 AN: 1386310 Hom.: 1377 Cov.: 28 AF XY: 0.0429 AC XY: 29595 AN XY: 690410

African (AFR) AF: 0.00682 AC: 219 AN: 32108

American (AMR) AF: 0.123 AC: 4987 AN: 40566

Ashkenazi Jewish (ASJ) AF: 0.0238 AC: 606 AN: 25478

East Asian (EAS) AF: 0.000237 AC: 9 AN: 38038

South Asian (SAS) AF: 0.0145 AC: 1198 AN: 82836

European-Finnish (FIN) AF: 0.0584 AC: 2167 AN: 37100

Middle Eastern (MID) AF: 0.0248 AC: 101 AN: 4066

European-Non Finnish (NFE) AF: 0.0461 AC: 49258 AN: 1068166

Other (OTH) AF: 0.0357 AC: 2071 AN: 57952

GnomAD4 genome AF: 0.0385 AC: 5860 AN: 152250 Hom.: 178 Cov.: 32 AF XY: 0.0389 AC XY: 2896 AN XY: 74430

African (AFR) AF: 0.00895 AC: 372 AN: 41564

American (AMR) AF: 0.0850 AC: 1301 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0242 AC: 84 AN: 3472

East Asian (EAS) AF: 0.000581 AC: 3 AN: 5164

South Asian (SAS) AF: 0.0130 AC: 63 AN: 4828

European-Finnish (FIN) AF: 0.0522 AC: 555 AN: 10624

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.0499 AC: 3390 AN: 67980

Other (OTH) AF: 0.0350 AC: 74 AN: 2116

Alfa AF: 0.0453 Hom.: 29

Bravo AF: 0.0394

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

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:3

-

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Sep 25, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Polycystic kidney disease, adult type Benign:2

May 11, 2020

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 02, 2017

Athena Diagnostics

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.Ala341Ala variant was identified in 36 of 1504 proband chromosomes (frequency: 0.024) from French, Australian, Dutch, British, and American individuals or families with ADPKD (Bataille 22008521, McCluskey 2002, Peters 2001, Rossetti 2001, Tan 2009, Rossetti 2012). The variant was identified in dbSNP (ID: rs11643513) as “NA”, ADPKD Mutation Database (classification likely neutral), but was not in Clinvitae, ClinVar, GeneInsight COGR, MutDB, PKD1-LOVD, and PKD1-LOVD 3.0. This variant was identified in the 1000 Genomes Project in 130 of 5000 chromosomes (frequency: 0.026), HAPMAP populations: AMR in 66 of 694 chromosomes (frequency: 0.0951) and EUR in 53 of 1006 chromosomes (frequency: 0.0527)/-SAS in 9 or 978 chromosomes (frequency: 0.0092), and in the Exome Aggregation Consortium database (March 14, 2016) in all populations except East Asian: European (Finnish) in 2 of 8 chromosomes (frequency: 0.25), Latino in 18 of 154 chromosomes (frequency: 0.1169), Other in 6 of 120 chromosomes (frequency: 0.05), European (Non-Finnish) in 132 of 2930 chromosomes (frequency: 0.0461), South Asian in 109 of 6226 chromosomes (frequency: 0.0174) and African in 5 of 436 chromosomes (frequency: 0.0115), increasing the likelihood this could be a low frequency benign variant. However we are not able to rule out that variant data from control databases is specific to PKD1 and not from one of the six PKD1 pseudogenes. The p.Ala341Ala 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. 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 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: Benign

Review Status: criteria provided, single submitter

Collection Method: research

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	1.2
DANN	Benign	0.73
PhyloP100		-1.1
PromoterAI		0.011	Neutral
Mutation Taster		=100/0	polymorphism (auto)

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: rs11643513; hg19: chr16-2167970; COSMIC: COSV51926039; COSMIC: COSV51926039;