rs376283361

Variant names:

• chr16-2106458-G-A
• rs376283361
• NM_001009944.3:c.7429C>T

Your query was ambiguous. Multiple possible variants found:

• chr16-2106458-G-A
• chr16-2106458-G-C

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4 BP6 BS1 BS2

The NM_001009944.3(PKD1):​c.7429C>T​(p.Arg2477Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000768 in 1,590,394 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R2477H) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00063 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00078 (3 hom.)
• Consequence: PKD1 NM_001009944.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:6
• Conservation: PhyloP100: 1.94
• Publications: 5 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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.27638018).
• BP6: Variant 16-2106458-G-A is Benign according to our data. Variant chr16-2106458-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 257000.We mark this variant Likely_benign, oryginal submission is: [Conflicting_classifications_of_pathogenicity].
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00063 (96/152314) while in subpopulation SAS AF = 0.00207 (10/4834). AF 95% confidence interval is 0.00112. There are 0 homozygotes in GnomAd4. There are 46 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 3 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PKD1	NM_001009944.3	c.7429C>T	p.Arg2477Cys	missense_variant	Exon 18 of 46	ENST00000262304.9	NP_001009944.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PKD1	ENST00000262304.9	c.7429C>T	p.Arg2477Cys	missense_variant	Exon 18 of 46	1	NM_001009944.3	ENSP00000262304.4

Frequencies

GnomAD3 genomes AF: 0.000631 AC: 96 AN: 152196 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00207

Gnomad FIN AF: 0.00179

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000823

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.00118 AC: 220 AN: 186738 AF XY: 0.00142

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000337

Gnomad ASJ exome AF: 0.00224

Gnomad EAS exome AF: 0.0000691

Gnomad FIN exome AF: 0.00222

Gnomad NFE exome AF: 0.000995

Gnomad OTH exome AF: 0.000404

GnomAD4 exome AF: 0.000783 AC: 1126 AN: 1438080 Hom.: 3 Cov.: 33 AF XY: 0.000870 AC XY: 622 AN XY: 715086

African (AFR) AF: 0.0000302 AC: 1 AN: 33156

American (AMR) AF: 0.000277 AC: 12 AN: 43266

Ashkenazi Jewish (ASJ) AF: 0.00170 AC: 44 AN: 25850

East Asian (EAS) AF: 0.0000511 AC: 2 AN: 39126

South Asian (SAS) AF: 0.00307 AC: 260 AN: 84802

European-Finnish (FIN) AF: 0.00289 AC: 121 AN: 41810

Middle Eastern (MID) AF: 0.00364 AC: 15 AN: 4126

European-Non Finnish (NFE) AF: 0.000546 AC: 604 AN: 1106358

Other (OTH) AF: 0.00112 AC: 67 AN: 59586

GnomAD4 genome AF: 0.000630 AC: 96 AN: 152314 Hom.: 0 Cov.: 32 AF XY: 0.000618 AC XY: 46 AN XY: 74490

African (AFR) AF: 0.0000241 AC: 1 AN: 41562

American (AMR) AF: 0.000261 AC: 4 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00144 AC: 5 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00207 AC: 10 AN: 4834

European-Finnish (FIN) AF: 0.00179 AC: 19 AN: 10628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000823 AC: 56 AN: 68014

Other (OTH) AF: 0.000473 AC: 1 AN: 2116

Alfa AF: 0.00110 Hom.: 0

Bravo AF: 0.000499

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000463 AC: 3

ExAC AF: 0.00109 AC: 124

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:6

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2 Benign:3

-

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The PKD1 p.R2477C variant was identified in a family with polycystickidney disease along with an F3168L variant, however only the F3168L variant segregated with disease (Rossetti_2007_PMID:17582161). The variant was also identified in dbSNP (ID: rs376283361), ClinVar (classified as a VUS by GeneDx and Centre for Mendelian Genomics, University Medical Centre Ljubljana and as likely benign by Prevention Genetics), LOVD 3.0 (classified as likely benign) and the ADPKD Mutation Database (classified as likely neutral). The variant was identified in control databases in 248 of 218070 chromosomes at a frequency of 0.001137 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: South Asian in 83 of 26454 chromosomes (freq: 0.003138), European (Finnish) in 31 of 13408 chromosomes (freq: 0.002312), Ashkenazi Jewish in 21 of 9226 chromosomes (freq: 0.002276), European (non-Finnish) in 97 of 97806 chromosomes (freq: 0.000992), Other in 5 of 6038 chromosomes (freq: 0.000828), Latino in 10 of 30478 chromosomes (freq: 0.000328) and East Asian in 1 of 16028 chromosomes (freq: 0.000062), but was not observed in the African population. The p.Arg2477 residue is conserved in mammals and three of four computational analyses (SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -

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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

- -

May 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PKD1: PM5, BP4, BS1, BS2 -

Oct 08, 2015

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The R2477C variant in the PKD1 gene has been reported previously in an individual with polycystic kidney disease. However, this individual reportedly carried a second missense variant in the PKD1 gene that segregated with the disease, while the R2477C variant reportedly did not segregate with the disease (Rossetti et al., 2007). The R2477C variant was not observed at any significant frequency in approximately 4,800 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The R2477C variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is not conserved. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. A missense variant in the same residue (R2477H) has been reported in association with polycystic kidney disease type 1 (Chang et al., 2013), supporting the functional importance of this residue. We interpret R2477C as a variant of uncertain significance. -

not specified Benign:3

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PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 19, 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.7429C>T (p.Arg2477Cys) 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 0.0012 in 186738 control chromosomes, predominantly at a frequency of 0.0031 within the South Asian subpopulation in the gnomAD database. The observed variant frequency within South Asian control individuals in the gnomAD database 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 experimental evidence demonstrating its impact on protein function has been reported. ClinVar contains an entry for this variant (Variation ID: 257000). Based on the evidence outlined above, the variant was classified as likely benign. -

Nov 07, 2023

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Clubfoot;C0022680:Polycystic kidney disease;C0426790:Narrow chest;C3275899:Hyperechogenic kidneys Uncertain:1

Jan 01, 2017

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.22
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.30	T;.
Eigen	Uncertain	0.36
Eigen_PC	Uncertain	0.29
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.92	D;D
M_CAP	Pathogenic	0.97	D
MetaRNN	Benign	0.28	T;T
MetaSVM	Benign	-0.44	T
MutationAssessor	Uncertain	2.3	M;M
PhyloP100		1.9
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-2.2	N;N
REVEL	Uncertain	0.50
Sift	Benign	0.079	T;T
Sift4G	Uncertain	0.0060	D;D
Polyphen		1.0	D;D
Vest4		0.53
MVP		0.92
ClinPred		0.044	T
GERP RS		4.8
Varity_R		0.087
gMVP		0.49
Mutation Taster		=44/56	disease causing

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: rs376283361; hg19: chr16-2156459;