rs148852027

chr16-2110250-G-Achr16-2110250-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.4917C>T(p.Gly1639=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0019 in 1,611,986 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. G1639G) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0015 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0019 (6 hom.)
• Consequence: PKD1 NM_001009944.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -1.88

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=-0.9).
• BP6: Variant 16-2110250-G-A is Benign according to our data. Variant chr16-2110250-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 256971.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2110250-G-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-1.88 with no splicing effect.
• BS2: High AC in GnomAd at 235 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PKD1	NM_001009944.3	c.4917C>T	p.Gly1639=	synonymous_variant	15/46	ENST00000262304.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PKD1	ENST00000262304.9	c.4917C>T	p.Gly1639=	synonymous_variant	15/46	1	NM_001009944.3	P5

Frequencies

GnomAD3 genomes AF: 0.00154 AC: 235 AN: 152232 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000338

Gnomad AMI AF: 0.00329

Gnomad AMR AF: 0.00118

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00285

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.00137 AC: 335 AN: 244598 Hom.: 0 AF XY: 0.00129 AC XY: 173 AN XY: 133708

Gnomad AFR exome AF: 0.000198

Gnomad AMR exome AF: 0.00143

Gnomad ASJ exome AF: 0.000505

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000327

Gnomad FIN exome AF: 0.0000940

Gnomad NFE exome AF: 0.00231

Gnomad OTH exome AF: 0.00218

GnomAD4 exome AF: 0.00193 AC: 2824 AN: 1459636 Hom.: 6 Cov.: 36 AF XY: 0.00190 AC XY: 1381 AN XY: 726094

Gnomad4 AFR exome AF: 0.000239

Gnomad4 AMR exome AF: 0.00141

Gnomad4 ASJ exome AF: 0.000727

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000429

Gnomad4 FIN exome AF: 0.000365

Gnomad4 NFE exome AF: 0.00233

Gnomad4 OTH exome AF: 0.00143

GnomAD4 genome AF: 0.00154 AC: 235 AN: 152350 Hom.: 0 Cov.: 33 AF XY: 0.00142 AC XY: 106 AN XY: 74496

Gnomad4 AFR AF: 0.000337

Gnomad4 AMR AF: 0.00118

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00285

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00234 Hom.: 0

Bravo AF: 0.00156

EpiCase AF: 0.00229

EpiControl AF: 0.00219

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2023	PKD1: BP4, BP7 -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 01, 2021	- -
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	Athena Diagnostics	May 29, 2018	- -

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

Polycystic kidney disease, adult type Benign:1

Benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Feb 27, 2020

- -

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.Gly1639= variant was not identified in the literature nor was it identified in the databases GeneInsight-COGR or PKD1-LOVD. The variant was identified in dbSNP (ID: rs148852027) as "With Likely benign allele", ClinVar (2x, likely benign), Clinvitae, LOVD 3.0 (1x), and the ADPKD Mutation Database (likely neutral). The variant was identified in control databases in 387 of 271600 chromosomes at a frequency of 0.001 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). Breakdown of the observations by population include African in 7 of 23132 chromosomes (freq: 0.0003), Other in 11 of 6314 chromosomes (freq: 0.002), Latino in 53 of 34320 chromosomes (freq: 0.002), European in 298 of 123000 chromosomes (freq: 0.002), Ashkenazi Jewish in 3 of 10006 chromosomes (freq: 0.0003), Finnish in 5 of 25308 chromosomes (freq: 0.0002), and South Asian in 10 of 30744 chromosomes (freq: 0.0003). The variant was not observed in the East Asian population. In addition we cannot be certain that data from control databases is specific to PKD1 and not from one of the six PKD1 pseudogenes. The p.Gly1639= 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 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	-0.90
Cadd	Benign	0.091
Dann	Benign	0.60

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: rs148852027; hg19: chr16-2160251;