rs143690392

Positions:

• chr16-2111149-G-A

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_001009944.3(PKD1):​c.4018C>T​(p.Arg1340Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00358 in 1,611,100 control chromosomes in the GnomAD database, including 15 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 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. R1340Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0031 (2 hom., cov: 33)
  • Exomes 𝑓: 0.0036 (13 hom.)
• Consequence: PKD1 NM_001009944.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -0.303

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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.036586612).
• BP6: Variant 16-2111149-G-A is Benign according to our data. Variant chr16-2111149-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 256960.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2111149-G-A is described in Lovd as [Likely_benign].
• BS2: High AC in GnomAd4 at 469 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PKD1	NM_001009944.3	c.4018C>T	p.Arg1340Trp	missense_variant	15/46	ENST00000262304.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PKD1	ENST00000262304.9	c.4018C>T	p.Arg1340Trp	missense_variant	15/46	1	NM_001009944.3	P5

Frequencies

GnomAD3 genomes AF: 0.00307 AC: 467 AN: 152204 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.00171

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00281

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00442

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00435

Gnomad OTH AF: 0.000955

GnomAD3 exomes AF: 0.00256 AC: 631 AN: 246614 Hom.: 2 AF XY: 0.00244 AC XY: 328 AN XY: 134528

Gnomad AFR exome AF: 0.00237

Gnomad AMR exome AF: 0.000987

Gnomad ASJ exome AF: 0.000804

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000131

Gnomad FIN exome AF: 0.00472

Gnomad NFE exome AF: 0.00390

Gnomad OTH exome AF: 0.00265

GnomAD4 exome AF: 0.00364 AC: 5306 AN: 1458778 Hom.: 13 Cov.: 36 AF XY: 0.00354 AC XY: 2568 AN XY: 725756

Gnomad4 AFR exome AF: 0.00215

Gnomad4 AMR exome AF: 0.000850

Gnomad4 ASJ exome AF: 0.000881

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000580

Gnomad4 FIN exome AF: 0.00386

Gnomad4 NFE exome AF: 0.00431

Gnomad4 OTH exome AF: 0.00292

GnomAD4 genome AF: 0.00308 AC: 469 AN: 152322 Hom.: 2 Cov.: 33 AF XY: 0.00267 AC XY: 199 AN XY: 74482

Gnomad4 AFR AF: 0.00176

Gnomad4 AMR AF: 0.00281

Gnomad4 ASJ AF: 0.00173

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00442

Gnomad4 NFE AF: 0.00435

Gnomad4 OTH AF: 0.000945

Alfa AF: 0.00379 Hom.: 1

Bravo AF: 0.00258

ESP6500AA AF: 0.00114 AC: 5

ESP6500EA AF: 0.00408 AC: 35

ExAC AF: 0.00241 AC: 291

EpiCase AF: 0.00436

EpiControl AF: 0.00296

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:7

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Dec 21, 2017	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2023	PKD1: BP4, BS1, BS2 -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely 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	GeneDx	Feb 10, 2021	This variant is associated with the following publications: (PMID: 22008521, 26489027, 11967008, 22995991, 27499327) -

Polycystic kidney disease, adult type Benign:2

Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Apr 03, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Apr 08, 2022	- -

Polycystic kidney disease Benign:1

Benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The PKD1 p.Arg1340Trp variant was identified in 5 of 328 proband chromosomes (frequency: 0.015) from individuals or families with ADPKD (Bataille 2011, Garcia-Gonzalez 2007, Rossetti 2002, Rossetti 2007). The variant was also identified in dbSNP (ID: rs143690392) as “NA”, and ADPKD Mutation Database (as likely neutral). This variant was identified in the 1000 Genomes Project in 10 of 5000 chromosomes (freq. 0.002), the NHLBI GO Exome Sequencing Project in 35 of 8582 European American alleles (freq. 0.004) and in 5 of 4374 African American alleles (freq. 0.001), the Exome Aggregation Consortium database (August 8, 2016) in 286 (1 homozygous) of 116868 chromosomes (freq. 0.002) in the following populations Finnish in 36 of 6204 chromosomes (freq. 0.006), European (Non-Finnish) in 220 of 63994 chromosomes (freq. 0.003), other in 2 of 838 chromosomes (freq. 0.002), African in 21 of 9516 chromosomes (freq. 0.002), Latino in 6 of 11372 chromosomes (freq. 0.0005), and South Asian in 1 of 16460 chromosomes (freq. 0.00006), but was not seen in East Asian populations, increasing the likelihood this could be a low frequency benign variant. In addition we cannot be certain that data from control databases is specific to PKD1 and not from one of the six PKD1 pseudogenes. The variant was not identified in Clinvitae, ClinVar, GeneInsight COGR, MutDB, PKD1-LOVD, and PKD1-LOVD 3.0. The p.Arg1340 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. The variant occurs outside of the splicing consensus sequence and 1 in 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a difference in splicing. The variant was identified with a co-occurring pathogenic PKD1 variant p.Leu56ProfsX60, increasing the likelihood that the p.Arg2191His variant does not have clinical significance. In addition, the variant was classified as “a known exonic polymorphism” in multiple studies (Rossetti 2012, Bataille 2011). In summary, based on the above information, this variant meets our laboratory criteria to be classified as benign. -

PKD1-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 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	0.066
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	5.1
DANN	Benign	0.92
DEOGEN2	Benign	0.22	T;.
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.057	N
LIST_S2	Benign	0.29	T;T
M_CAP	Pathogenic	0.29	D
MetaRNN	Benign	0.037	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.90	L;L
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.19	T
PROVEAN	Benign	-1.4	N;N
REVEL	Uncertain	0.29
Sift	Benign	0.16	T;T
Sift4G	Benign	0.17	T;T
Polyphen		0.032	B;B
Vest4		0.71
MVP		0.99
ClinPred		0.0025	T
GERP RS		-7.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.056
gMVP		0.38

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: rs143690392; hg19: chr16-2161150;