16-2114809-G-C

Position:

• chr16-2114809-G-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001009944.3(PKD1):​c.2214C>G​(p.Pro738=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00672 in 979,188 control chromosomes in the GnomAD database, including 311 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.026 (196 hom., cov: 32)
  • Exomes 𝑓: 0.0031 (115 hom.)
• Consequence: PKD1 NM_001009944.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.527

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 16-2114809-G-C is Benign according to our data. Variant chr16-2114809-G-C is described in ClinVar as [Benign]. Clinvar id is 256931.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2114809-G-C is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-0.527 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0889 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PKD1	NM_001009944.3	c.2214C>G	p.Pro738=	synonymous_variant	11/46	ENST00000262304.9	NP_001009944.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PKD1	ENST00000262304.9	c.2214C>G	p.Pro738=	synonymous_variant	11/46	1	NM_001009944.3	ENSP00000262304	P5
PKD1	ENST00000423118.5	c.2214C>G	p.Pro738=	synonymous_variant	11/46	1		ENSP00000399501	A2
PKD1	ENST00000488185.2	c.472+2680C>G		intron_variant		5		ENSP00000456672
PKD1	ENST00000568591.5	c.*542C>G		3_prime_UTR_variant, NMD_transcript_variant	7/12	2		ENSP00000457162

Frequencies

GnomAD3 genomes AF: 0.0264 AC: 4007 AN: 151976 Hom.: 196 Cov.: 32

Gnomad AFR AF: 0.0915

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00858

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00318

Gnomad NFE AF: 0.000648

Gnomad OTH AF: 0.0201

GnomAD3 exomes AF: 0.00639 AC: 799 AN: 125016 Hom.: 37 AF XY: 0.00476 AC XY: 321 AN XY: 67460

Gnomad AFR exome AF: 0.0977

Gnomad AMR exome AF: 0.00618

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000993

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000351

Gnomad OTH exome AF: 0.00256

GnomAD4 exome AF: 0.00311 AC: 2572 AN: 827098 Hom.: 115 Cov.: 11 AF XY: 0.00250 AC XY: 1063 AN XY: 424462

Gnomad4 AFR exome AF: 0.0925

Gnomad4 AMR exome AF: 0.00708

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000108

Gnomad4 FIN exome AF: 0.0000307

Gnomad4 NFE exome AF: 0.000280

Gnomad4 OTH exome AF: 0.00813

GnomAD4 genome AF: 0.0264 AC: 4010 AN: 152090 Hom.: 196 Cov.: 32 AF XY: 0.0250 AC XY: 1859 AN XY: 74366

Gnomad4 AFR AF: 0.0913

Gnomad4 AMR AF: 0.00857

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.0000942

Gnomad4 NFE AF: 0.000648

Gnomad4 OTH AF: 0.0199

Alfa AF: 0.00162 Hom.: 3

Bravo AF: 0.0297

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Jan 29, 2016	- -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Oct 11, 2017	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 26, 2019	This variant is associated with the following publications: (PMID: 17574468, 22008521) -

Polycystic kidney disease, adult type Benign:1

Benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Jun 02, 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.Pro738Pro variant was identified in 1 of 74 proband chromosomes (frequency: 0.014) from unrelated individuals or families with ADPKD, and was not identified in 100 control chromosomes from healthy individuals (Bataille 2011). The variant is listed in the dbSNP database (ID#: rs543166733), however no frequency information was provided. This variant is also listed in the 1000 Genomes Project in 174 of 5014 chromosomes (frequency: 0.035). The variant was identified in the Exome Aggregation Consortium database (March 14 2106) in 49 of 7068 chromosomes (freq. 0.007) in the following populations: African in 46 (1 homozygous) of 494 chromosomes (freq. 0.09), Latino in 2 of 142 chromosomes (freq. 0.01), other in 1 of 88 chromosomes (freq. 0.01), but was not seen in East Asian, Finish, European (Non-Finnish) and South Asian populations, increasing the likelihood this could be a low frequency benign variant. We cannot be certain that variant data from control databases is specific to PKD1 and not from one of the six PKD1 pseudogenes. The variant is identified In GeneInsight COGR 1x as benign and by the ADPKD Mutation Database 4x as likely neutral. The p.Pro738Pro variant is not expected to have clinical significance because it does not result in a change of amino acid and is not located in a known consensus splice site. In addition, in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.048
DANN	Benign	0.45

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: rs543166733; hg19: chr16-2164810;