rs367983387

chr16-2116541-G-Achr16-2116541-G-Cchr16-2116541-G-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001009944.3(PKD1):c.1710C>T(p.His570=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00638 in 1,540,920 control chromosomes in the GnomAD database, including 44 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0057 (2 hom., cov: 33)
  • Exomes 𝑓: 0.0065 (42 hom.)
• Consequence: PKD1 NM_001009944.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.710

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=-0.88).
• BP6: Variant 16-2116541-G-A is Benign according to our data. Variant chr16-2116541-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 256926.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2116541-G-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-0.71 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00566 (862/152282) while in subpopulation NFE AF= 0.00776 (528/68006). AF 95% confidence interval is 0.00722. There are 2 homozygotes in gnomad4. There are 447 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 862 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PKD1	NM_001009944.3	c.1710C>T	p.His570=	synonymous_variant	8/46	ENST00000262304.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PKD1	ENST00000262304.9	c.1710C>T	p.His570=	synonymous_variant	8/46	1	NM_001009944.3	P5
PKD1	ENST00000423118.5	c.1710C>T	p.His570=	synonymous_variant	8/46	1		A2
PKD1	ENST00000488185.2	c.472+948C>T		intron_variant		5
PKD1	ENST00000568591.5	c.*38C>T		3_prime_UTR_variant, NMD_transcript_variant	4/12	2

Frequencies

GnomAD3 genomes AF: 0.00566 AC: 862 AN: 152164 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.00135

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.000392

Gnomad ASJ AF: 0.00375

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00186

Gnomad FIN AF: 0.0231

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00776

Gnomad OTH AF: 0.00192

GnomAD3 exomes AF: 0.00498 AC: 857 AN: 172122 Hom.: 6 AF XY: 0.00530 AC XY: 497 AN XY: 93836

Gnomad AFR exome AF: 0.000841

Gnomad AMR exome AF: 0.000393

Gnomad ASJ exome AF: 0.00320

Gnomad EAS exome AF: 0.0000750

Gnomad SAS exome AF: 0.00307

Gnomad FIN exome AF: 0.0208

Gnomad NFE exome AF: 0.00691

Gnomad OTH exome AF: 0.00296

GnomAD4 exome AF: 0.00646 AC: 8976 AN: 1388638 Hom.: 42 Cov.: 30 AF XY: 0.00644 AC XY: 4436 AN XY: 688646

Gnomad4 AFR exome AF: 0.000880

Gnomad4 AMR exome AF: 0.000464

Gnomad4 ASJ exome AF: 0.00376

Gnomad4 EAS exome AF: 0.0000271

Gnomad4 SAS exome AF: 0.00284

Gnomad4 FIN exome AF: 0.0220

Gnomad4 NFE exome AF: 0.00689

Gnomad4 OTH exome AF: 0.00530

GnomAD4 genome AF: 0.00566 AC: 862 AN: 152282 Hom.: 2 Cov.: 33 AF XY: 0.00600 AC XY: 447 AN XY: 74452

Gnomad4 AFR AF: 0.00135

Gnomad4 AMR AF: 0.000392

Gnomad4 ASJ AF: 0.00375

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00186

Gnomad4 FIN AF: 0.0231

Gnomad4 NFE AF: 0.00776

Gnomad4 OTH AF: 0.00190

Alfa AF: 0.00556 Hom.: 4

Bravo AF: 0.00382

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Polycystic kidney disease, adult type Benign:3

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	May 23, 2017	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Apr 01, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Sep 23, 2021	- -

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 18, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2023	PKD1: BP4, BP7, BS2 -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Feb 01, 2017

- -

Polycystic kidney disease Benign:1

Benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The PKD1 p.His570His variant was identified in 8 of 860 proband chromosomes (frequency: 0.009) from individuals or families with ADPKD (Rossetti 2001, Rossetti 2002, Rossetti 2012, Garcia-Gonzalez 2007). The variant was also identified in dbSNP (ID: rs367983387) as “NA”, Clinvitae (classified as variant of unknown significance by Emory Genetics), and in the ADPKD Mutation Database (classification likely neutral); in the 1000 Genomes Project in 17 of 5000 chromosomes (frequency: 0.0034), in HAP-MAP: HAPMAP-EUR in 15 of 1006 chromosomes (frequency: 0.0149), HAPMAP-AMR in 1 of 694 chromosomes (frequency: 0.0014), HAPMAP-EAS in 1 of 1008 chromosomes (frequency: 0.001), NHLBI GO Exome Sequencing Project (ESP) in 40 of 8462 (frequency: 0.0047) European American, and in 3 of 4308 (frequency: 0.0007) African American alleles. The variant was also identified in the Exome Aggregation Consortium database (March 14, 2016) in 19 of 130 chromosomes (frequency: 0.1462) from a population of European (Finnish) individuals, in 164 (2 homozygous) of 7450 chromosomes (frequency: 0.02201) from a population of European (Non-Finnish) individuals, in 34 of 8056 chromosomes (frequency: 0.0042) from a population of South Asians, and in 3 of 1762 chromosomes (frequency: 0.0017) from a population of African individuals, increasing the likelihood this could be a low frequency benign variant. The variant was not seen in the East Asian, Other or Latino poulations. The variant was identified by our laboratory in a patient with PKD with a co-occurring pathogenic PKD1 variant (c.8388T>G, p.Tyr2796X), increasing the likelihood that the p.His570His variant does not have clinical significance. The p.His570His 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, this variant meets our laboratory criteria to be classified as benign. -

PKD1-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 20, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
Cadd	Benign	5.5
Dann	Benign	0.54
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs367983387; hg19: chr16-2166542; COSMIC: COSV99237287; COSMIC: COSV99237287;