NM_001009944.3:c.8440G>A

Variant names:

• chr16-2103617-C-T
• rs149151043
• NM_001009944.3:c.8440G>A

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001009944.3(PKD1):​c.8440G>A​(p.Gly2814Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00735 in 1,610,450 control chromosomes in the GnomAD database, including 62 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. G2814G) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0062 (5 hom., cov: 31)
  • Exomes 𝑓: 0.0075 (57 hom.)
• Consequence: PKD1 NM_001009944.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 1.55
• 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]

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 -18 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 6 uncertain in NM_001009944.3
• BP4: Computational evidence support a benign effect (MetaRNN=0.0081606805).
• BP6: Variant 16-2103617-C-T is Benign according to our data. Variant chr16-2103617-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 257021.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0062 (944/152302) while in subpopulation NFE AF = 0.00859 (584/68018). AF 95% confidence interval is 0.00801. There are 5 homozygotes in GnomAd4. There are 495 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 5 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PKD1	NM_001009944.3	c.8440G>A	p.Gly2814Arg	missense_variant	Exon 23 of 46	ENST00000262304.9	NP_001009944.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PKD1	ENST00000262304.9	c.8440G>A	p.Gly2814Arg	missense_variant	Exon 23 of 46	1	NM_001009944.3	ENSP00000262304.4

Frequencies

GnomAD3 genomes AF: 0.00621 AC: 945 AN: 152184 Hom.: 5 Cov.: 31

Gnomad AFR AF: 0.00125

Gnomad AMI AF: 0.00439

Gnomad AMR AF: 0.00720

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.0171

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00858

Gnomad OTH AF: 0.00525

GnomAD2 exomes AF: 0.00611 AC: 1520 AN: 248758 AF XY: 0.00605

Gnomad AFR exome AF: 0.00163

Gnomad AMR exome AF: 0.00417

Gnomad ASJ exome AF: 0.000401

Gnomad EAS exome AF: 0.000491

Gnomad FIN exome AF: 0.0175

Gnomad NFE exome AF: 0.00818

Gnomad OTH exome AF: 0.00659

GnomAD4 exome AF: 0.00747 AC: 10891 AN: 1458148 Hom.: 57 Cov.: 34 AF XY: 0.00714 AC XY: 5178 AN XY: 725392

African (AFR) AF: 0.00105 AC: 35 AN: 33402

American (AMR) AF: 0.00490 AC: 219 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.000421 AC: 11 AN: 26126

East Asian (EAS) AF: 0.000302 AC: 12 AN: 39694

South Asian (SAS) AF: 0.000197 AC: 17 AN: 86164

European-Finnish (FIN) AF: 0.0166 AC: 862 AN: 52048

Middle Eastern (MID) AF: 0.00290 AC: 12 AN: 4136

European-Non Finnish (NFE) AF: 0.00841 AC: 9345 AN: 1111692

Other (OTH) AF: 0.00628 AC: 378 AN: 60176

GnomAD4 genome AF: 0.00620 AC: 944 AN: 152302 Hom.: 5 Cov.: 31 AF XY: 0.00665 AC XY: 495 AN XY: 74456

African (AFR) AF: 0.00123 AC: 51 AN: 41584

American (AMR) AF: 0.00719 AC: 110 AN: 15304

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5148

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4830

European-Finnish (FIN) AF: 0.0171 AC: 182 AN: 10624

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00859 AC: 584 AN: 68018

Other (OTH) AF: 0.00520 AC: 11 AN: 2116

Alfa AF: 0.00445 Hom.: 0

Bravo AF: 0.00544

TwinsUK AF: 0.00836 AC: 31

ALSPAC AF: 0.0106 AC: 41

ESP6500AA AF: 0.00137 AC: 6

ESP6500EA AF: 0.00828 AC: 71

ExAC AF: 0.00553 AC: 665

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

-

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jun 18, 2025

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

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: PKD1 c.8440G>A (p.Gly2814Arg) results in a non-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 0.0061 in 248758 control chromosomes in the gnomAD database, including 7 homozygotes. The observed variant frequency exceeds the estimated maximal expected allele frequency for a pathogenic variant in PKD1 causing PKD1-Biallelic Autosomal Recessive Polycystic Kidney Disease phenotype. To our knowledge, no occurrence of c.8440G>A in individuals affected with PKD1-Biallelic Autosomal Recessive Polycystic Kidney Disease and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 257021). Based on the evidence outlined above, the variant was classified as likely benign. -

-

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

Mar 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PKD1: BS2 -

Mar 10, 2020

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 17574468, 12007219, 24374109, 18837007) -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Polycystic kidney disease, adult type Benign:2

Sep 13, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 26, 2018

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: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

The PKD1 p.Gly2814Arg variant was identified in 29 of 1202 proband chromosomes (frequency: 0.024) from individuals or families with ADPKD (Garcia-Gonzalez 2007, Inoue 2002, Rossetti 2001, Rossetti 2002, Rossetti 2012, Tan 2008). The variant was also identified in dbSNP (ID: rs149151043) as "With other allele ", ClinVar (classified as benign by ARUP and Prevention Genetics), LOVD 3.0 (2x as benign or with unknown effect), and in ADPKD Mutation Database (likely neutral). The variant was not identified in COGR, or PKD1-LOVD databases. The variant was identified in control databases in 1715 of 275482 chromosomes (7 homozygous) at a frequency of 0.006 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 34 of 23822 chromosomes (freq: 0.0014), Other in 43 of 6430 chromosomes (freq: 0.0066), Latino in 146 of 34410 chromosomes (freq: 0.004), European in 1016 of 125388 chromosomes (freq: 0.008), Ashkenazi Jewish in 4 of 10094 chromosomes (freq: 0.00039), East Asian in 9 of 18840 chromosomes (freq: 0.00047), Finnish in 458 of 25724 chromosomes (freq: 0.017), and South Asian in 5 of 30774 chromosomes (freq: 0.00016). 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 p.Gly2814 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and 1 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In addition, the variant was identified with a co-occurring pathogenic PKD1 or PKD2 variants (PKD1 p.Glu2810*, p.Ile3109fs*, c.7704-1G>T; and PKD2 p.Arg872*), increasing the likelihood that the p.Gly2814Arg variant does not have clinical significance (Garcia-Gonzalez 2007). In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign. -

Autosomal dominant polycystic kidney disease Benign:1

Jan 01, 2019

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

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: research

- -

PKD1-related disorder Benign:1

Sep 05, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.31	T;.
Eigen	Uncertain	0.25
Eigen_PC	Uncertain	0.27
FATHMM_MKL	Benign	0.54	D
LIST_S2	Benign	0.62	T;T
MetaRNN	Benign	0.0082	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.8	L;L
PhyloP100		1.5
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-2.2	N;N
REVEL	Benign	0.17
Sift	Benign	0.072	T;T
Sift4G	Uncertain	0.020	D;D
Polyphen		0.99	D;D
Vest4		0.63
MutPred		0.48		Loss of catalytic residue at G2814 (P = 0.021);Loss of catalytic residue at G2814 (P = 0.021);
MVP		0.74
ClinPred		0.013	T
GERP RS		3.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.068
gMVP		0.56
Mutation Taster		=80/20	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: rs149151043; hg19: chr16-2153618; COSMIC: COSV99032366; COSMIC: COSV99032366;