16-2093545-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBP6BS1

The NM_001009944.3(PKD1):c.11015G>A(p.Arg3672Gln) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000637 in 1,597,364 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 17/24 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. 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. R3672W) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00038 ( 1 hom., cov: 33)

Exomes 𝑓: 0.00066 ( 1 hom. )

Consequence

PKD1
NM_001009944.3 missense, splice_region

Scores

Splicing: ADA: 0.0002232

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:5

Conservation

PhyloP100: 0.633

Publications

4 publications found

Variant links:

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 links:

PKD1-AS1 (HGNC:56035): (PKD1 antisense RNA 1)

PKD1-AS1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.049121976).

BP6

Variant 16-2093545-C-T is Benign according to our data. Variant chr16-2093545-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 440102.

BS1

Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.000664 (960/1445072) while in subpopulation MID AF = 0.00125 (7/5614). AF 95% confidence interval is 0.000744. There are 1 homozygotes in GnomAdExome4. There are 472 alleles in the male GnomAdExome4 subpopulation. Median coverage is 32. This position passed quality control check.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PKD1	NM_001009944.3 link	c.11015G>A	p.Arg3672Gln	missense_variant, splice_region_variant	Exon 37 of 46	ENST00000262304.9	NP_001009944.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PKD1	ENST00000262304.9 link	c.11015G>A	p.Arg3672Gln	missense_variant, splice_region_variant	Exon 37 of 46	1	NM_001009944.3	ENSP00000262304.4		P98161-1

Frequencies

GnomAD3 genomes

AF:

0.000381

AC:

AN:

152172

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000145

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00318

Gnomad NFE

AF:

0.000691

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000402

AC:

AN:

223828

AF XY:

0.000462

show subpopulations

Gnomad AFR exome

AF:

0.000215

Gnomad AMR exome

AF:

0.000186

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000675

Gnomad OTH exome

AF:

0.000358

GnomAD4 exome

AF:

0.000664

AC:

960

AN:

1445072

Hom.:

Cov.:

AF XY:

0.000658

AC XY:

472

AN XY:

717298

show subpopulations

African (AFR)

AF:

0.000180

AC:

AN:

33276

American (AMR)

AF:

0.000211

AC:

AN:

42726

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25752

East Asian (EAS)

AF:

0.00

AC:

AN:

39042

South Asian (SAS)

AF:

0.000394

AC:

AN:

83716

European-Finnish (FIN)

AF:

0.0000392

AC:

AN:

50984

Middle Eastern (MID)

AF:

0.00125

AC:

AN:

5614

European-Non Finnish (NFE)

AF:

0.000788

AC:

870

AN:

1104178

Other (OTH)

AF:

0.000552

AC:

AN:

59784

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.490

Heterozygous variant carriers

149

198

248

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

120

150

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000381

AC:

AN:

152292

Hom.:

Cov.:

AF XY:

0.000336

AC XY:

AN XY:

74454

show subpopulations

African (AFR)

AF:

0.000144

AC:

AN:

41562

American (AMR)

AF:

0.000196

AC:

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.000193

AC:

AN:

5176

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000691

AC:

AN:

68006

Other (OTH)

AF:

0.00

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000850

Hom.:

Bravo

AF:

0.000544

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.000456

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:1Benign:1

Feb 01, 2019

Athena Diagnostics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 02, 2025

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

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: PKD1 c.11015G>A (p.Arg3672Gln) results in a conservative amino acid change in the encoded protein sequence near the exon 37 / intron 37 5' splice donor site. Four of five in-silico tools predict a benign effect of the variant on protein function. Consensus agreement among computation tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.0004 in 223828 control chromosomes in the gnomAD database, including 1 homozygote. This frequency is not significantly higher than estimated for a pathogenic variant in PKD1 causing PKD1-Biallelic Autosomal Recessive Polycystic Kidney Disease, allowing no conclusion about variant significance. To our knowledge, c.11015G>A has not been observed in individual(s) affected with PKD1-Biallelic Autosomal Recessive Polycystic Kidney Disease and no experimental evidence demonstrating an impact on protein function has been reported. ClinVar contains an entry for this variant (Variation ID: 440102). Based on the evidence outlined above, the variant was classified as uncertain significance. -

not provided

Benign:2

Oct 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PKD1: BP4, BS2 -

Jul 23, 2017

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Inborn genetic diseases

Uncertain:1

Sep 11, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.11012G>A (p.R3671Q) alteration is located in exon 37 (coding exon 37) of the PKD1 gene. This alteration results from a G to A substitution at nucleotide position 11012, causing the arginine (R) at amino acid position 3671 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

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.Arg3672Gln variant was not identified in the literature nor was it identified in the PKD1-LOVD. The variant was identified in dbSNP (ID: rs201220835) as "With other allele", ClinVar (classified as likely benign by ARUP; as uncertain significance by Athena Diagnostics), LOVD 3.0, and ADPKD Mutation Database (as likely neutral). The variant was also identified in our laboratory with a co-occurring pathogenic PKD1 variant (PKD1 c.5510G>A (p.Trp1837X)), increasing the likelihood that the p.Arg3672Gln variant does not have clinical significance. The variant was identified in control databases in 108 of 249596 chromosomes (2 homozygous) at a frequency of 0.0004 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 4 of 21718 chromosomes (freq: 0.0002), Other in 2 of 5944 chromosomes (freq: 0.0003), Latino in 6 of 32178 chromosomes (freq: 0.0002), European in 83 of 112264 chromosomes (freq: 0.000739), EastAsian in 1 of 17524 chromosomes (freq: 0.000057), and South Asian in 12 of 27884 chromosomes (freq: 0.0004), while the variant was not observed in the Ashkenazi Jewish, and Finnish, populations. The p.Arg3672 residue is not conserved in mammals and four out of five 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. The c.11015G>A variant occurs in the last three bases of the exon. This position has been shown to be part of the splicing consensus sequence and variants involving this position sometimes affect splicing. In addition, 2 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing. 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. -

PKD1-related disorder

Benign:1

Feb 16, 2022

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely 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

0.10

BayesDel_addAF

Benign

-0.43

BayesDel_noAF

Benign

-0.47

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.31

T;.

Eigen

Benign

-0.34

Eigen_PC

Benign

-0.44

FATHMM_MKL

Benign

0.59

LIST_S2

Benign

0.80

T;T

M_CAP

Benign

0.060

MetaRNN

Benign

0.049

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.2

L;.

PhyloP100

0.63

PrimateAI

Benign

0.31

PROVEAN

Benign

-2.1

N;N

REVEL

Benign

0.11

Sift

Uncertain

0.016

D;D

Sift4G

Uncertain

0.020

D;D

Polyphen

0.94

P;D

Vest4

0.42

MVP

0.64

ClinPred

0.10

GERP RS

-0.24

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.17

gMVP

0.37

Mutation Taster

=65/35

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00022

dbscSNV1_RF

Benign

0.12

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over