rs146887330

chr16-2111665-G-Achr16-2111665-G-C

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001009944.3(PKD1):c.3502C>T(p.Pro1168Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0177 in 1,574,942 control chromosomes in the GnomAD database, including 312 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/19 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. P1168A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.013 (21 hom., cov: 33)
  • Exomes 𝑓: 0.018 (291 hom.)
• Consequence: PKD1 NM_001009944.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.458

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 -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 1 benign, 5 uncertain in NM_001009944.3
• BP4: Computational evidence support a benign effect (MetaRNN=0.0032174885).
• BP6: Variant 16-2111665-G-A is Benign according to our data. Variant chr16-2111665-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 256953.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2111665-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0132 (2005/152250) while in subpopulation NFE AF= 0.0195 (1327/67990). AF 95% confidence interval is 0.0186. There are 21 homozygotes in gnomad4. There are 988 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 2005 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PKD1	NM_001009944.3	c.3502C>T	p.Pro1168Ser	missense_variant	15/46	ENST00000262304.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PKD1	ENST00000262304.9	c.3502C>T	p.Pro1168Ser	missense_variant	15/46	1	NM_001009944.3	P5

Frequencies

GnomAD3 genomes AF: 0.0132 AC: 2005 AN: 152132 Hom.: 21 Cov.: 33

Gnomad AFR AF: 0.00290

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.00321

Gnomad ASJ AF: 0.0190

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00642

Gnomad FIN AF: 0.0350

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0195

Gnomad OTH AF: 0.0163

GnomAD3 exomes AF: 0.0143 AC: 2619 AN: 183752 Hom.: 31 AF XY: 0.0146 AC XY: 1444 AN XY: 99168

Gnomad AFR exome AF: 0.00280

Gnomad AMR exome AF: 0.00449

Gnomad ASJ exome AF: 0.0229

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00901

Gnomad FIN exome AF: 0.0309

Gnomad NFE exome AF: 0.0193

Gnomad OTH exome AF: 0.00992

GnomAD4 exome AF: 0.0182 AC: 25844 AN: 1422692 Hom.: 291 Cov.: 36 AF XY: 0.0177 AC XY: 12460 AN XY: 704446

Gnomad4 AFR exome AF: 0.00251

Gnomad4 AMR exome AF: 0.00449

Gnomad4 ASJ exome AF: 0.0198

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00934

Gnomad4 FIN exome AF: 0.0285

Gnomad4 NFE exome AF: 0.0202

Gnomad4 OTH exome AF: 0.0134

GnomAD4 genome AF: 0.0132 AC: 2005 AN: 152250 Hom.: 21 Cov.: 33 AF XY: 0.0133 AC XY: 988 AN XY: 74436

Gnomad4 AFR AF: 0.00289

Gnomad4 AMR AF: 0.00320

Gnomad4 ASJ AF: 0.0190

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00684

Gnomad4 FIN AF: 0.0350

Gnomad4 NFE AF: 0.0195

Gnomad4 OTH AF: 0.0162

Alfa AF: 0.0128 Hom.: 15

Bravo AF: 0.0107

ESP6500AA AF: 0.00376 AC: 16

ESP6500EA AF: 0.0142 AC: 120

ExAC AF: 0.0112 AC: 1316

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	- -

Polycystic kidney disease, adult type Benign:2

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	May 31, 2017	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Mar 16, 2020	- -

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

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Dec 02, 2019

This variant is associated with the following publications: (PMID: 18640754) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.089
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.55
Cadd	Benign	7.3
Dann	Benign	0.93
DEOGEN2	Benign	0.17	T;.
Eigen	Benign	-0.60
Eigen_PC	Benign	-0.58
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.79	T;T
MetaRNN	Benign	0.0032	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.95	L;L
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-0.78	N;N
REVEL	Benign	0.068
Sift	Benign	0.38	T;T
Sift4G	Benign	0.27	T;T
Polyphen		0.21	B;P
Vest4		0.092
ClinPred		0.0030	T
GERP RS		3.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.074
gMVP		0.27

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs146887330; hg19: chr16-2161666;