rs140869992

chr16-2108569-G-Achr16-2108569-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001009944.3(PKD1):c.6598C>T(p.Arg2200Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0137 in 1,568,720 control chromosomes in the GnomAD database, including 167 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 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. R2200H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0090 (8 hom., cov: 33)
  • Exomes 𝑓: 0.014 (159 hom.)
• Consequence: PKD1 NM_001009944.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 1.44

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0055719614).
• BP6: Variant 16-2108569-G-A is Benign according to our data. Variant chr16-2108569-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 256990.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2108569-G-A is described in Lovd as [Benign]. Variant chr16-2108569-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00903 (1375/152308) while in subpopulation NFE AF= 0.0143 (973/67998). AF 95% confidence interval is 0.0136. There are 8 homozygotes in gnomad4. There are 604 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd at 1376 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PKD1	NM_001009944.3	c.6598C>T	p.Arg2200Cys	missense_variant	15/46	ENST00000262304.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PKD1	ENST00000262304.9	c.6598C>T	p.Arg2200Cys	missense_variant	15/46	1	NM_001009944.3	P5

Frequencies

GnomAD3 genomes AF: 0.00904 AC: 1376 AN: 152190 Hom.: 8 Cov.: 33

Gnomad AFR AF: 0.00253

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00681

Gnomad ASJ AF: 0.0245

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.0110

Gnomad FIN AF: 0.00301

Gnomad MID AF: 0.00637

Gnomad NFE AF: 0.0143

Gnomad OTH AF: 0.0100

GnomAD3 exomes AF: 0.0112 AC: 2030 AN: 180444 Hom.: 13 AF XY: 0.0115 AC XY: 1128 AN XY: 97686

Gnomad AFR exome AF: 0.00168

Gnomad AMR exome AF: 0.00752

Gnomad ASJ exome AF: 0.0219

Gnomad EAS exome AF: 0.000148

Gnomad SAS exome AF: 0.0124

Gnomad FIN exome AF: 0.00379

Gnomad NFE exome AF: 0.0159

Gnomad OTH exome AF: 0.0133

GnomAD4 exome AF: 0.0142 AC: 20116 AN: 1416412 Hom.: 159 Cov.: 34 AF XY: 0.0138 AC XY: 9649 AN XY: 700358

Gnomad4 AFR exome AF: 0.00238

Gnomad4 AMR exome AF: 0.00738

Gnomad4 ASJ exome AF: 0.0199

Gnomad4 EAS exome AF: 0.0000266

Gnomad4 SAS exome AF: 0.0112

Gnomad4 FIN exome AF: 0.00432

Gnomad4 NFE exome AF: 0.0158

Gnomad4 OTH exome AF: 0.0138

GnomAD4 genome AF: 0.00903 AC: 1375 AN: 152308 Hom.: 8 Cov.: 33 AF XY: 0.00811 AC XY: 604 AN XY: 74488

Gnomad4 AFR AF: 0.00253

Gnomad4 AMR AF: 0.00680

Gnomad4 ASJ AF: 0.0245

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.0110

Gnomad4 FIN AF: 0.00301

Gnomad4 NFE AF: 0.0143

Gnomad4 OTH AF: 0.00946

Alfa AF: 0.00864 Hom.: 2

Bravo AF: 0.00905

TwinsUK AF: 0.0162 AC: 60

ALSPAC AF: 0.0205 AC: 79

ESP6500AA AF: 0.00264 AC: 11

ESP6500EA AF: 0.0138 AC: 113

ExAC AF: 0.00913 AC: 1005

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 28, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: frequency -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

Polycystic kidney disease, adult type Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Mar 15, 2022	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Dec 02, 2019	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 02, 2019	This variant is associated with the following publications: (PMID: 22383692, 17574468, 18791038, 12842373, 18837007, 26632257, 27499327, 32823016) -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2022	PKD1: BP4, BS1, BS2 -

Polycystic kidney disease Benign:1

Benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The PKD1 p.Arg2200Cys variant was identified in 10 of 678 proband chromosomes (frequency: 0.015) from Chinese and North American individuals or families with ADPKD (Liu 2015, Garcia-Gonzalez 2007, Rossetti, Tan 2009). The variant was identified with co-occurring pathogenic PKD1 variants (N116fsX and IVS24+5G>C), in 2 individuals who each had 5-7 identified variants, increasing the likelihood that the p.Arg2200Cys variant does not have clinical significance (Garcia-Gonzalez 2007). The variant was also identified in dbSNP (ID: rs140869992) as “NA”, ADPKD Mutation Database (classification “likely neutral”), in the 1000 Genomes Project in 36 of 5000 chromosomes (frequency: 0.0072), HAP-MAP populations: EUR in 17 of 1006 chromosomes (frequency: 0.0169), SAS in 15 of 978 chromosomes (frequency: 0.0153), AMR in 4 of 694 chromosomes (frequency: 0.0058), in NHLBI GO Exome Sequencing Project in 113 of 8182 (frequency: 0.0138) European American alleles, in 11 of 4170 African American alleles (frequency: 0.0026), and in all populations in the Exome Aggregation Consortium database (March 14 2016) in 755 of 42138 alleles (frequency 0.018) or in European (Non-Finnish) in 534 (1 homozygous) of 20712 (frequency: 0.0258), other populations in 6 of 314 (frequency: 0.0191), South Asian in 160 (1 homozygous) of 10450 (frequency: 0.0015), Latino in 36 of 2818 (frequency: 0.0128), European (Finnish) in 7 of 1456 (frequency: 0.0048), African in 11 of 3512 (frequency: 0.0003), and East Asian in 1 of 2876 alleles (frequency: 00003), increasing the likelihood this could be a low frequency benign variant. The p.Arg2200residue is 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 2 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In summary, based on the above information, this variant meets our laboratory criteria to be classified as benign. -

Autosomal dominant polycystic kidney disease Benign:1

Likely benign, criteria provided, single submitter

research

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

Jan 01, 2019

- -

PKD1-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 05, 2019

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	0.22
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.35
Cadd	Benign	23
Dann	Uncertain	1.0
DEOGEN2	Benign	0.29	T;.
Eigen	Benign	-0.097
Eigen_PC	Benign	-0.28
FATHMM_MKL	Benign	0.27	N
LIST_S2	Uncertain	0.87	D;D
MetaRNN	Benign	0.0056	T;T
MetaSVM	Benign	-0.76	T
MutationAssessor	Uncertain	2.1	M;M
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-1.5	N;N
REVEL	Benign	0.23
Sift	Benign	0.046	D;D
Sift4G	Uncertain	0.028	D;D
Polyphen		1.0	D;D
Vest4		0.39
ClinPred		0.012	T
GERP RS		3.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Varity_R		0.087
gMVP		0.50

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

Publications

LitVar

Other links and lift over

dbSNP: rs140869992; hg19: chr16-2158570; COSMIC: COSV51914844; COSMIC: COSV51914844;