16-2114788-G-C

Position:

• chr16-2114788-G-C

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_001009944.3(PKD1):​c.2235C>G​(p.Ala745Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00183 in 1,221,926 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0014 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0019 (2 hom.)
• Consequence: PKD1 NM_001009944.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 0.392

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 -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 16-2114788-G-C is Benign according to our data. Variant chr16-2114788-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 256932.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2114788-G-C is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=0.392 with no splicing effect.
• BS2: High AC in GnomAd4 at 216 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PKD1	NM_001009944.3	c.2235C>G	p.Ala745Ala	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.2235C>G	p.Ala745Ala	synonymous_variant	11/46	1	NM_001009944.3	ENSP00000262304.4

Frequencies

GnomAD3 genomes AF: 0.00142 AC: 216 AN: 152070 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000604

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.000577

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000828

Gnomad FIN AF: 0.000377

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00265

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00115 AC: 150 AN: 130066 Hom.: 0 AF XY: 0.00124 AC XY: 87 AN XY: 70412

Gnomad AFR exome AF: 0.000468

Gnomad AMR exome AF: 0.0000827

Gnomad ASJ exome AF: 0.000254

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00135

Gnomad FIN exome AF: 0.000200

Gnomad NFE exome AF: 0.00218

Gnomad OTH exome AF: 0.000744

GnomAD4 exome AF: 0.00189 AC: 2021 AN: 1069744 Hom.: 2 Cov.: 15 AF XY: 0.00189 AC XY: 1019 AN XY: 539086

Gnomad4 AFR exome AF: 0.000481

Gnomad4 AMR exome AF: 0.000142

Gnomad4 ASJ exome AF: 0.000475

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000995

Gnomad4 FIN exome AF: 0.000120

Gnomad4 NFE exome AF: 0.00233

Gnomad4 OTH exome AF: 0.00123

GnomAD4 genome AF: 0.00142 AC: 216 AN: 152182 Hom.: 0 Cov.: 32 AF XY: 0.00128 AC XY: 95 AN XY: 74402

Gnomad4 AFR AF: 0.000602

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.000577

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000829

Gnomad4 FIN AF: 0.000377

Gnomad4 NFE AF: 0.00265

Gnomad4 OTH AF: 0.00

Alfa AF: 0.00109 Hom.: 0

Bravo AF: 0.00123

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:6

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 09, 2020	This variant is associated with the following publications: (PMID: 22008521, 22383692) -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2022	PKD1: BP4, BP7 -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Feb 04, 2020	- -

Polycystic kidney disease, adult type Benign:1

Benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Apr 19, 2019

- -

Polycystic kidney disease Benign:1

Likely benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The PKD1 p.Ala745Ala variant was identified in 3 of 534 proband chromosomes (frequency: 0.006) from individuals or families with ADPKD, however both of these studies identified the variant as a polymorphism (Bataille 2011, Rossetti 2012). The variant was also identified in dbSNP (ID: rs533569454) as “NA”, the ADPKD Mutation Database (as likely neutral), the 1000 Genomes Project in 5 of 5000 chromosomes (frequency: 0.001), and the Exome Aggregation Consortium database (March 14, 2016) in 17 of 10152 chromosomes (freq. 0.001675) in the following populations: South Asian in 12 of 6074 chromosomes (freq. 0.001976), European (Non-Finnish) in 5 of 3058 chromosomes (freq. 0.001635), but was not seen in African, East Asian, European (Finnish), or Latino populations, increasing the likelihood this could be a low frequency benign variant. However we cannot be certain that data from control databases is specific to PKD1 and not from one of the six PKD1 pseudogenes. The variant was not found in the Clinvitae, ClinVar, GeneInsight COGR, MutDB, PKD1-LOVD, and PKD1-LOVD 3.0 databases. The p.Ala745Ala 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. Futher more 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 likely benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	2.6
DANN	Benign	0.51

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: rs533569454; hg19: chr16-2164789;