rs146096401

chr16-2108671-G-Achr16-2108671-G-C

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.6496C>T(p.Arg2166Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00195 in 1,566,168 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. R2166R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0027 (5 hom., cov: 33)
  • Exomes 𝑓: 0.0019 (8 hom.)
• Consequence: PKD1 NM_001009944.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 4.69

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=0.009762377).
• BP6: Variant 16-2108671-G-A is Benign according to our data. Variant chr16-2108671-G-A is described in ClinVar as [Benign]. Clinvar id is 256989.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2108671-G-A is described in Lovd as [Benign]. Variant chr16-2108671-G-A is described in Lovd as [Likely_benign].
• BS2: High AC in GnomAd at 413 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PKD1	NM_001009944.3	c.6496C>T	p.Arg2166Cys	missense_variant	15/46	ENST00000262304.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PKD1	ENST00000262304.9	c.6496C>T	p.Arg2166Cys	missense_variant	15/46	1	NM_001009944.3	P5

Frequencies

GnomAD3 genomes AF: 0.00271 AC: 413 AN: 152236 Hom.: 5 Cov.: 33

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000578

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0285

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00144

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.00324 AC: 580 AN: 179062 Hom.: 4 AF XY: 0.00299 AC XY: 288 AN XY: 96288

Gnomad AFR exome AF: 0.0000939

Gnomad AMR exome AF: 0.000181

Gnomad ASJ exome AF: 0.000114

Gnomad EAS exome AF: 0.000529

Gnomad SAS exome AF: 0.000204

Gnomad FIN exome AF: 0.0231

Gnomad NFE exome AF: 0.00243

Gnomad OTH exome AF: 0.00231

GnomAD4 exome AF: 0.00187 AC: 2640 AN: 1413816 Hom.: 8 Cov.: 34 AF XY: 0.00174 AC XY: 1219 AN XY: 699206

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000233

Gnomad4 ASJ exome AF: 0.0000790

Gnomad4 EAS exome AF: 0.000243

Gnomad4 SAS exome AF: 0.0000867

Gnomad4 FIN exome AF: 0.0203

Gnomad4 NFE exome AF: 0.00141

Gnomad4 OTH exome AF: 0.00145

GnomAD4 genome AF: 0.00270 AC: 412 AN: 152352 Hom.: 5 Cov.: 33 AF XY: 0.00391 AC XY: 291 AN XY: 74506

Gnomad4 AFR AF: 0.000120

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000579

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0285

Gnomad4 NFE AF: 0.00143

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.00105 Hom.: 0

Bravo AF: 0.000748

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.000233 AC: 1

ESP6500EA AF: 0.00153 AC: 13

ExAC AF: 0.00263 AC: 310

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 20, 2020	This variant is associated with the following publications: (PMID: 26632257, 17574468) -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2022	PKD1: BP4, BS1, BS2 -

Polycystic kidney disease, adult type Benign:2

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Apr 15, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Mendelics	Aug 22, 2023	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.35
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Uncertain	0.070
Cadd	Pathogenic	32
Dann	Pathogenic	1.0
DEOGEN2	Benign	0.42	T;.
Eigen	Pathogenic	0.73
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.94	D;D
MetaRNN	Benign	0.0098	T;T
MetaSVM	Benign	-0.82	T
MutationAssessor	Uncertain	2.6	M;M
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.57	T
PROVEAN	Uncertain	-2.7	D;D
REVEL	Uncertain	0.31
Sift	Uncertain	0.014	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;D
Vest4		0.78
MVP		0.91
ClinPred		0.057	T
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.20
gMVP		0.67

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: rs146096401; hg19: chr16-2158672;