16-2110903-C-T

Variant names:

• chr16-2110903-C-T
• rs140980374
• NM_001009944.3:c.4264G>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.4264G>A​(p.Ala1422Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00544 in 1,611,388 control chromosomes in the GnomAD database, including 52 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A1422D) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0050 (4 hom., cov: 33)
  • Exomes 𝑓: 0.0055 (48 hom.)
• Consequence: PKD1 NM_001009944.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -0.0600
• Publications: 10 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 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 8 uncertain in NM_001009944.3
• BP4: Computational evidence support a benign effect (MetaRNN=0.004206896).
• BP6: Variant 16-2110903-C-T is Benign according to our data. Variant chr16-2110903-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 256964.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00498 (758/152302) while in subpopulation AMR AF = 0.0066 (101/15300). AF 95% confidence interval is 0.00565. There are 4 homozygotes in GnomAd4. There are 361 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 4 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PKD1	NM_001009944.3	c.4264G>A	p.Ala1422Thr	missense_variant	Exon 15 of 46	ENST00000262304.9	NP_001009944.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PKD1	ENST00000262304.9	c.4264G>A	p.Ala1422Thr	missense_variant	Exon 15 of 46	1	NM_001009944.3	ENSP00000262304.4

Frequencies

GnomAD3 genomes AF: 0.00499 AC: 759 AN: 152184 Hom.: 4 Cov.: 33

Gnomad AFR AF: 0.00111

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00661

Gnomad ASJ AF: 0.0343

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00518

Gnomad FIN AF: 0.00113

Gnomad MID AF: 0.0475

Gnomad NFE AF: 0.00613

Gnomad OTH AF: 0.0110

GnomAD2 exomes AF: 0.00591 AC: 1472 AN: 248902 AF XY: 0.00603

Gnomad AFR exome AF: 0.000627

Gnomad AMR exome AF: 0.00385

Gnomad ASJ exome AF: 0.0337

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00152

Gnomad NFE exome AF: 0.00673

Gnomad OTH exome AF: 0.0102

GnomAD4 exome AF: 0.00549 AC: 8012 AN: 1459086 Hom.: 48 Cov.: 36 AF XY: 0.00550 AC XY: 3989 AN XY: 725832

African (AFR) AF: 0.00179 AC: 60 AN: 33432

American (AMR) AF: 0.00391 AC: 175 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.0313 AC: 818 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00428 AC: 369 AN: 86188

European-Finnish (FIN) AF: 0.00150 AC: 78 AN: 52104

Middle Eastern (MID) AF: 0.0489 AC: 233 AN: 4762

European-Non Finnish (NFE) AF: 0.00521 AC: 5796 AN: 1111812

Other (OTH) AF: 0.00802 AC: 483 AN: 60244

GnomAD4 genome AF: 0.00498 AC: 758 AN: 152302 Hom.: 4 Cov.: 33 AF XY: 0.00485 AC XY: 361 AN XY: 74462

African (AFR) AF: 0.00111 AC: 46 AN: 41564

American (AMR) AF: 0.00660 AC: 101 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0343 AC: 119 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5184

South Asian (SAS) AF: 0.00518 AC: 25 AN: 4824

European-Finnish (FIN) AF: 0.00113 AC: 12 AN: 10626

Middle Eastern (MID) AF: 0.0476 AC: 14 AN: 294

European-Non Finnish (NFE) AF: 0.00613 AC: 417 AN: 68016

Other (OTH) AF: 0.0109 AC: 23 AN: 2112

Alfa AF: 0.00733 Hom.: 9

Bravo AF: 0.00506

ESP6500AA AF: 0.00205 AC: 9

ESP6500EA AF: 0.00838 AC: 72

ExAC AF: 0.00593 AC: 717

Asia WGS AF: 0.00289 AC: 10 AN: 3478

EpiCase AF: 0.00872

EpiControl AF: 0.00836

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:5

Oct 08, 2020

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 17582161, 22383692) -

-

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

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

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

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PKD1: BP4, BS2 -

not specified Benign:2

-

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

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.4264G>A (p.Ala1422Thr) 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 0.0059 in 248902 control chromosomes in the gnomAD database, including 12 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. c.4264G>A has been observed in individuals affected with Polycystic Kidney Disease (e.g., Rossetti_2007, Alzahrani_2022). These reports do not provide unequivocal conclusions about association of the variant with PKD1-Biallelic Autosomal Recessive Polycystic Kidney Disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 36422197, 17582161). ClinVar contains an entry for this variant (Variation ID: 256964). Based on the evidence outlined above, the variant was classified as likely benign. -

Polycystic kidney disease, adult type Benign:1

Dec 20, 2019

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

PKD1, EXON15, c.4264G>A, p.Ala1422Thr, (Alias c.4475G>A), Heterozygous, Benign The PKD1 p.Ala1422Thr variant was identified in 3 of 864 proband chromosomes (frequency: 0.003) from individuals or families with ADPKD, and was not identified in 242 control chromosomes from healthy individuals (Rossetti 2007, Rossetti 2012). The variant was also identified in dbSNP (ID: rs140980374) “With clinical significance allele not available”, in 1000 Genomes Project in 22 of 5000 chromosomes (frequency: 0.004), in NHLBI GO Exome Sequencing Project (ESP) in 72 of 8592 European American (frequency: 0.008) and 9 in 4394 (frequency: 0.002) African American alleles. This variant was identified in the Exome Aggregation Consortium database (March 2016) in 713 (5 homozygous) of 118566 chromosomes (freq. 0.006) in the following populations: other in 10 of 880 chromosomes (freq. 0.01), European (Non-Finnish) in 565 of 64594 chromosomes (freq. 0.009), South Asian in 76 of 16504 chromosomes (freq. 0.005), Latino in 45 of 11538 chromosomes (freq. 0.004), Finnish in 7 of 6602 chromosomes (freq. 0.001), and African in 10 of 9854 chromosomes (freq. 0.001), but was not seen in the East Asian populations, increasing the likelihood this could be a low frequency benign variant. However we cannot be certain that variant data from control databases is specific to PKD1 and not from one of the six PKD1 pseudogenes. Furthermore, the variant is listed in the GeneInsight COGR database as benign, as likely neutral in the ADPKD Mutation Database, and listed with no classification in the PKD1-LOVD 3.0 database. The p.Ala1422 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. Furthermore, the variant amino acid “Threonine” is present in macaque, increasing the likelihood that this variant does not have clinical significance. Computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein. 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. The variant was observed as co-occurring with another pathogenic variant in one individual identified by our laboratory, increasing the likelihood this variant does not have clinical significance. In summary, based on the above information, this variant is 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: 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	0.068
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	0.13
DANN	Benign	0.58
DEOGEN2	Benign	0.15	T;.
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.088	N
LIST_S2	Benign	0.24	T;T
MetaRNN	Benign	0.0042	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.090	N;N
PhyloP100		-0.060
PrimateAI	Benign	0.31	T
PROVEAN	Benign	0.14	N;N
REVEL	Benign	0.018
Sift	Benign	0.41	T;T
Sift4G	Benign	0.47	T;T
Polyphen		0.083	B;B
Vest4		0.085
MVP		0.55
ClinPred		0.00098	T
GERP RS		-1.8
Varity_R		0.027
gMVP		0.16
Mutation Taster		=83/17	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: rs140980374; hg19: chr16-2160904;