rs116092985

chr16-2110972-A-Gchr16-2110972-A-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001009944.3(PKD1):c.4195T>C(p.Trp1399Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0843 in 1,597,052 control chromosomes in the GnomAD database, including 6,826 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. W1399Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.078 (563 hom., cov: 33)
  • Exomes 𝑓: 0.085 (6263 hom.)
• Consequence: PKD1 NM_001009944.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 0.237

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=0.0042101443).
• BP6: Variant 16-2110972-A-G is Benign according to our data. Variant chr16-2110972-A-G is described in ClinVar as [Benign]. Clinvar id is 256962.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2110972-A-G is described in Lovd as [Benign]. Variant chr16-2110972-A-G is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0956 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PKD1	NM_001009944.3	c.4195T>C	p.Trp1399Arg	missense_variant	15/46	ENST00000262304.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PKD1	ENST00000262304.9	c.4195T>C	p.Trp1399Arg	missense_variant	15/46	1	NM_001009944.3	P5

Frequencies

GnomAD3 genomes AF: 0.0778 AC: 11846 AN: 152206 Hom.: 563 Cov.: 33

Gnomad AFR AF: 0.0505

Gnomad AMI AF: 0.123

Gnomad AMR AF: 0.0848

Gnomad ASJ AF: 0.151

Gnomad EAS AF: 0.000770

Gnomad SAS AF: 0.0261

Gnomad FIN AF: 0.0760

Gnomad MID AF: 0.165

Gnomad NFE AF: 0.0975

Gnomad OTH AF: 0.0942

GnomAD3 exomes AF: 0.0650 AC: 15796 AN: 243130 Hom.: 783 AF XY: 0.0657 AC XY: 8696 AN XY: 132400

Gnomad AFR exome AF: 0.0404

Gnomad AMR exome AF: 0.0545

Gnomad ASJ exome AF: 0.135

Gnomad EAS exome AF: 0.0000551

Gnomad SAS exome AF: 0.0269

Gnomad FIN exome AF: 0.0677

Gnomad NFE exome AF: 0.0850

Gnomad OTH exome AF: 0.0930

GnomAD4 exome AF: 0.0850 AC: 122750 AN: 1444728 Hom.: 6263 Cov.: 36 AF XY: 0.0839 AC XY: 60294 AN XY: 718702

Gnomad4 AFR exome AF: 0.0468

Gnomad4 AMR exome AF: 0.0596

Gnomad4 ASJ exome AF: 0.139

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.0301

Gnomad4 FIN exome AF: 0.0684

Gnomad4 NFE exome AF: 0.0937

Gnomad4 OTH exome AF: 0.0855

GnomAD4 genome AF: 0.0778 AC: 11849 AN: 152324 Hom.: 563 Cov.: 33 AF XY: 0.0741 AC XY: 5521 AN XY: 74472

Gnomad4 AFR AF: 0.0505

Gnomad4 AMR AF: 0.0847

Gnomad4 ASJ AF: 0.151

Gnomad4 EAS AF: 0.000772

Gnomad4 SAS AF: 0.0261

Gnomad4 FIN AF: 0.0760

Gnomad4 NFE AF: 0.0976

Gnomad4 OTH AF: 0.0932

Alfa AF: 0.0814 Hom.: 242

Bravo AF: 0.0795

TwinsUK AF: 0.0963 AC: 357

ALSPAC AF: 0.0929 AC: 358

ExAC AF: 0.0662 AC: 8003

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 01, 2017	- -

Polycystic kidney disease, adult type Benign:1

Benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Jul 07, 2020

- -

Polycystic kidney disease Benign:1

Benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The PKD1, p.Trp1399Arg variant was identified in 6.7% of 11722 control alleles in the Exome Aggregation Consortium (March 14, 2016). This variant was identified by our laboratory with a co-occurring pathogenic PKD1 variant (c.11798_11810del, p.Leu3933ArgfsX8), in a patient with PKD increasing the likelihood that the p.Ala3512Val variant does not have clinical significance. 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

Benign, criteria provided, single submitter

research

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

Jan 01, 2019

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Dec 30, 2019

This variant is associated with the following publications: (PMID: 24374109) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.044
BayesDel_addAF	Benign	-0.68	T
BayesDel_noAF	Benign	-0.68
Cadd	Benign	4.9
Dann	Benign	0.44
DEOGEN2	Benign	0.14	T;.
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.014	N
LIST_S2	Benign	0.055	T;T
MetaRNN	Benign	0.0042	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-1.6	N;N
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.22	T
PROVEAN	Benign	1.1	N;N
REVEL	Benign	0.091
Sift	Benign	0.36	T;T
Sift4G	Benign	0.69	T;T
Polyphen		0.0	B;B
Vest4		0.021
MutPred		0.60		Loss of catalytic residue at W1399 (P = 0.0152);Loss of catalytic residue at W1399 (P = 0.0152);
ClinPred		0.0042	T
GERP RS		3.4
Varity_R		0.057
gMVP		0.33

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: rs116092985; hg19: chr16-2160973; COSMIC: COSV51916806; COSMIC: COSV51916806;