rs148164067

chr16-2110621-C-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.4546G>A(p.Ala1516Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00673 in 1,610,296 control chromosomes in the GnomAD database, including 38 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0050 (2 hom., cov: 33)
  • Exomes 𝑓: 0.0069 (36 hom.)
• Consequence: PKD1 NM_001009944.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -1.71

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=0.010074973).
• BP6: Variant 16-2110621-C-T is Benign according to our data. Variant chr16-2110621-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 256967.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2110621-C-T is described in Lovd as [Benign]. Variant chr16-2110621-C-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00498 (758/152310) while in subpopulation NFE AF= 0.00766 (521/68018). AF 95% confidence interval is 0.00712. There are 2 homozygotes in gnomad4. There are 363 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd at 759 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PKD1	NM_001009944.3	c.4546G>A	p.Ala1516Thr	missense_variant	15/46	ENST00000262304.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PKD1	ENST00000262304.9	c.4546G>A	p.Ala1516Thr	missense_variant	15/46	1	NM_001009944.3	P5

Frequencies

GnomAD3 genomes AF: 0.00499 AC: 759 AN: 152192 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.00135

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000981

Gnomad ASJ AF: 0.0153

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00414

Gnomad FIN AF: 0.00828

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00766

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.00576 AC: 1430 AN: 248178 Hom.: 5 AF XY: 0.00584 AC XY: 789 AN XY: 135060

Gnomad AFR exome AF: 0.000818

Gnomad AMR exome AF: 0.000869

Gnomad ASJ exome AF: 0.0156

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00435

Gnomad FIN exome AF: 0.00919

Gnomad NFE exome AF: 0.00775

Gnomad OTH exome AF: 0.00627

GnomAD4 exome AF: 0.00691 AC: 10077 AN: 1457986 Hom.: 36 Cov.: 36 AF XY: 0.00687 AC XY: 4981 AN XY: 725228

Gnomad4 AFR exome AF: 0.00102

Gnomad4 AMR exome AF: 0.00116

Gnomad4 ASJ exome AF: 0.0160

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00447

Gnomad4 FIN exome AF: 0.00976

Gnomad4 NFE exome AF: 0.00742

Gnomad4 OTH exome AF: 0.00655

GnomAD4 genome AF: 0.00498 AC: 758 AN: 152310 Hom.: 2 Cov.: 33 AF XY: 0.00488 AC XY: 363 AN XY: 74458

Gnomad4 AFR AF: 0.00135

Gnomad4 AMR AF: 0.000980

Gnomad4 ASJ AF: 0.0153

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00414

Gnomad4 FIN AF: 0.00828

Gnomad4 NFE AF: 0.00766

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00730 Hom.: 2

Bravo AF: 0.00414

ESP6500AA AF: 0.00160 AC: 7

ESP6500EA AF: 0.00711 AC: 61

ExAC AF: 0.00605 AC: 731

EpiCase AF: 0.00780

EpiControl AF: 0.00670

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

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	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 12, 2020	This variant is associated with the following publications: (PMID: 17574468, 18640754, 22383692, 18837007, 22008521) -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2023	PKD1: BP4, BS2 -

not specified Benign:3

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Feb 04, 2020	- -
Benign, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	- -

Polycystic kidney disease, adult type Benign:1

Benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Apr 01, 2020

- -

PKD1-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 01, 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	0.070
BayesDel_addAF	Benign	-0.63	T
BayesDel_noAF	Benign	-0.68
Cadd	Benign	0.0030
Dann	Benign	0.81
DEOGEN2	Benign	0.14	T;.
Eigen	Benign	-2.0
Eigen_PC	Benign	-2.0
FATHMM_MKL	Benign	0.022	N
LIST_S2	Benign	0.29	T;T
M_CAP	Benign	0.066	D
MetaRNN	Benign	0.010	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.10	N;N
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.32	T
PROVEAN	Benign	0.57	N;N
REVEL	Benign	0.017
Sift	Benign	0.51	T;T
Sift4G	Benign	0.51	T;T
Polyphen		0.083	B;B
Vest4		0.15
MVP		0.61
ClinPred		0.0043	T
GERP RS		-8.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.021
gMVP		0.22

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: rs148164067; hg19: chr16-2160622;