16-2112360-A-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 2P and 20B. PM1BP4_StrongBP6_Very_StrongBA1

The NM_001009944.3(PKD1):c.3275T>C(p.Met1092Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0875 in 1,514,852 control chromosomes in the GnomAD database, including 13,074 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 nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

Frequency

Genomes: 𝑓 0.20 ( 5154 hom., cov: 33)

Exomes 𝑓: 0.075 ( 7920 hom. )

Consequence

PKD1
NM_001009944.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 2.85

Publications

17 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 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

PKD1 links:

ENSG00000261240 (HGNC:):

ENSG00000261240 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -18 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 benign, 10 uncertain in NM_001009944.3

BP4

Computational evidence support a benign effect (MetaRNN=0.020166844).

BP6

Variant 16-2112360-A-G is Benign according to our data. Variant chr16-2112360-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 256947.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.457 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PKD1	NM_001009944.3 link	c.3275T>C	p.Met1092Thr	missense_variant	Exon 14 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.3275T>C	p.Met1092Thr	missense_variant	Exon 14 of 46	1	NM_001009944.3	ENSP00000262304.4		P98161-1

Frequencies

GnomAD3 genomes

AF:

0.197

AC:

29974

AN:

152056

Hom.:

5135

Cov.:

show subpopulations

Gnomad AFR

AF:

0.462

Gnomad AMI

AF:

0.123

Gnomad AMR

AF:

0.136

Gnomad ASJ

AF:

0.159

Gnomad EAS

AF:

0.000578

Gnomad SAS

AF:

0.0284

Gnomad FIN

AF:

0.0758

Gnomad MID

AF:

0.187

Gnomad NFE

AF:

0.0991

Gnomad OTH

AF:

0.192

GnomAD2 exomes

AF:

0.0721

AC:

15410

AN:

213684

AF XY:

0.0656

show subpopulations

Gnomad AFR exome

AF:

0.397

Gnomad AMR exome

AF:

0.0671

Gnomad ASJ exome

AF:

0.105

Gnomad EAS exome

AF:

0.0000560

Gnomad FIN exome

AF:

0.0399

Gnomad NFE exome

AF:

0.0674

Gnomad OTH exome

AF:

0.0886

GnomAD4 exome

AF:

0.0752

AC:

102537

AN:

1362680

Hom.:

7920

Cov.:

AF XY:

0.0729

AC XY:

49520

AN XY:

678960

show subpopulations

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

African (AFR)

AF:

0.434

AC:

11896

AN:

27384

American (AMR)

AF:

0.0757

AC:

3259

AN:

43076

Ashkenazi Jewish (ASJ)

AF:

0.125

AC:

3057

AN:

24378

East Asian (EAS)

AF:

0.000176

AC:

AN:

39670

South Asian (SAS)

AF:

0.0259

AC:

2191

AN:

84614

European-Finnish (FIN)

AF:

0.0619

AC:

2297

AN:

37124

Middle Eastern (MID)

AF:

0.147

AC:

565

AN:

3852

European-Non Finnish (NFE)

AF:

0.0705

AC:

73737

AN:

1045430

Other (OTH)

AF:

0.0967

AC:

5528

AN:

57152

⚠️ 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.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.360

Heterozygous variant carriers

4335

8669

13004

17338

21673

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2452

4904

7356

9808

12260

<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:

0.197

AC:

30036

AN:

152172

Hom.:

5154

Cov.:

AF XY:

0.190

AC XY:

14124

AN XY:

74428

show subpopulations

African (AFR)

AF:

0.462

AC:

19152

AN:

41456

American (AMR)

AF:

0.136

AC:

2078

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.159

AC:

552

AN:

3470

East Asian (EAS)

AF:

0.000579

AC:

AN:

5182

South Asian (SAS)

AF:

0.0280

AC:

135

AN:

4828

European-Finnish (FIN)

AF:

0.0758

AC:

805

AN:

10618

Middle Eastern (MID)

AF:

0.194

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0991

AC:

6741

AN:

67998

Other (OTH)

AF:

0.190

AC:

401

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

1007

2014

3021

4028

5035

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

272

544

816

1088

1360

<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:

0.148

Hom.:

515

Bravo

AF:

0.217

ExAC

AF:

0.0712

AC:

8153

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 04, 2025

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

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Polycystic kidney disease, adult type

Benign:2

Jul 07, 2020

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 05, 2017

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Dec 30, 2019

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 22608885) -

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 c.3275T>C, p.Met1092Thr variant was identified in 7.5% of 6086 control alleles in the Exome Aggregation Consortium (March 14, 2016). According to ACMG guidelines for variant classification based on allele frequency, category BA1, this variant is considered benign and has not been further reviewed (Richards 2015). -

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

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.037

BayesDel_addAF

Benign

-0.60

BayesDel_noAF

Benign

-0.50

CADD

Benign

(source)

DANN

Benign

0.67

DEOGEN2

Benign

0.15

T;.

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.0020

LIST_S2

Benign

0.21

T;T

MetaRNN

Benign

0.020

T;T

MetaSVM

Benign

-0.90

MutationAssessor

Benign

-2.7

N;N

PhyloP100

2.9

PrimateAI

Benign

0.41

PROVEAN

Benign

2.5

N;N

REVEL

Benign

0.15

Sift

Benign

1.0

T;T

Sift4G

Benign

1.0

T;T

Polyphen

0.0010

B;B

Vest4

0.032

ClinPred

0.0033

GERP RS

4.4

PromoterAI

-0.011

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.044

gMVP

0.24

Mutation Taster

=96/4

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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