16-2102849-A-G

Variant names:

• chr16-2102849-A-G
• rs9926309
• NM_001009944.3:c.8913T>C

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_001009944.3(PKD1):​c.8913T>C​(p.Ala2971Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00547 in 1,594,920 control chromosomes in the GnomAD database, including 450 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.032 (241 hom., cov: 32)
  • Exomes 𝑓: 0.0029 (209 hom.)
• Consequence: PKD1 NM_001009944.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -1.96
• Publications: 3 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.036).
• BP6: Variant 16-2102849-A-G is Benign according to our data. Variant chr16-2102849-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 257031.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.96 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.108 is higher than 0.05.

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.8913T>C	p.Ala2971Ala	synonymous	Exon 24 of 46	NP_001009944.3
	PKD1	NM_000296.4		c.8913T>C	p.Ala2971Ala	synonymous	Exon 24 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.8913T>C	p.Ala2971Ala	synonymous	Exon 24 of 46	ENSP00000262304.4
	PKD1	ENST00000423118.5	TSL:1	c.8913T>C	p.Ala2971Ala	synonymous	Exon 24 of 46	ENSP00000399501.1
	PKD1	ENST00000480227.5	TSL:1	n.650T>C		non_coding_transcript_exon	Exon 2 of 8

Frequencies

GnomAD3 genomes AF: 0.0319 AC: 4444 AN: 139172 Hom.: 242 Cov.: 32

Gnomad AFR AF: 0.111

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0111

Gnomad ASJ AF: 0.000932

Gnomad EAS AF: 0.00107

Gnomad SAS AF: 0.000236

Gnomad FIN AF: 0.000101

Gnomad MID AF: 0.00680

Gnomad NFE AF: 0.000812

Gnomad OTH AF: 0.0299

GnomAD2 exomes AF: 0.00775 AC: 1928 AN: 248664 AF XY: 0.00559

Gnomad AFR exome AF: 0.102

Gnomad AMR exome AF: 0.00660

Gnomad ASJ exome AF: 0.000902

Gnomad EAS exome AF: 0.000163

Gnomad FIN exome AF: 0.0000472

Gnomad NFE exome AF: 0.000420

Gnomad OTH exome AF: 0.00279

GnomAD4 exome AF: 0.00293 AC: 4262 AN: 1455626 Hom.: 209 Cov.: 34 AF XY: 0.00248 AC XY: 1798 AN XY: 724176

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

African (AFR) AF: 0.0964 AC: 3147 AN: 32630

American (AMR) AF: 0.00738 AC: 328 AN: 44456

Ashkenazi Jewish (ASJ) AF: 0.000804 AC: 21 AN: 26114

East Asian (EAS) AF: 0.000227 AC: 9 AN: 39674

South Asian (SAS) AF: 0.000244 AC: 21 AN: 86010

European-Finnish (FIN) AF: 0.0000387 AC: 2 AN: 51724

Middle Eastern (MID) AF: 0.00484 AC: 20 AN: 4134

European-Non Finnish (NFE) AF: 0.000260 AC: 289 AN: 1110828

Other (OTH) AF: 0.00708 AC: 425 AN: 60056

⚠️ 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: 0.0320 AC: 4458 AN: 139294 Hom.: 241 Cov.: 32 AF XY: 0.0308 AC XY: 2089 AN XY: 67908

African (AFR) AF: 0.111 AC: 4187 AN: 37680

American (AMR) AF: 0.0111 AC: 153 AN: 13802

Ashkenazi Jewish (ASJ) AF: 0.000932 AC: 3 AN: 3220

East Asian (EAS) AF: 0.00108 AC: 5 AN: 4648

South Asian (SAS) AF: 0.000237 AC: 1 AN: 4226

European-Finnish (FIN) AF: 0.000101 AC: 1 AN: 9930

Middle Eastern (MID) AF: 0.00730 AC: 2 AN: 274

European-Non Finnish (NFE) AF: 0.000812 AC: 51 AN: 62798

Other (OTH) AF: 0.0294 AC: 55 AN: 1868

Alfa AF: 0.00818 Hom.: 15

Bravo AF: 0.0336

EpiCase AF: 0.000654

EpiControl AF: 0.000593

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

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

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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

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

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

not provided Benign:3

Oct 09, 2017

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

May 11, 2021

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 9285784, 17574468, 22008521, 22383692)

Polycystic kidney disease, adult type Benign:1

Jun 02, 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.Ala2971Ala variant was identified in 5 of 698 proband chromosomes (frequency: 0.007) from individuals or families with ADPKD, and was not identified in 442 control chromosomes from healthy individuals (Bataille_2011, Garcia-Gonzalez_2007, Rossetti_2012). The variant was also identified in dbSNP (ID: rs9926309) “With NA allele”, in 1000 Genomes Project in 190 of 5013 chromosomes (frequency: 0.0379), and in the NHLBI GO Exome Sequencing Project (ESP) in 5 of 8580 European American and in 394 of 4390 African American alleles. In addition, the variant is identified in the Exome Aggregation Consortium database (March 14, 2016) in 1155 of 119736 chromosomes (freq. 0.01) in the following populations: African in 1053 (57 homozygous) of 10158 chromosomes (freq. 0.1037), other in 5 of 886 chromosomes (freq. 0.006), Latino in 65 of 11538 chromosomes (freq. 0.006), European (Non-Finnish) in 29 of 65418 chromosomes (freq. 0.0004), South Asian in 2 of 16504 chromosomes (freq. 0.0001), East Asian in 1 of 6610 chromosomes (freq. 0.0001) but was not seen in a Finish population, increasing the likelihood this could be a low frequency benign variant. The variant is also listed in GeneInsight COGR (classified as benign), and in ADPKD Mutation Database (6x as likely neutral). The p.Ala2971Ala 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. In summary, based on the above information, this variant meets our laboratory criteria to be classified as benign.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.071
DANN	Benign	0.41
PhyloP100		-2.0
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: rs9926309; hg19: chr16-2152850;