chr16-2116537-G-A

Position:

• chr16-2116537-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001009944.3(PKD1):​c.1714C>T​(p.Pro572Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00624 in 1,530,406 control chromosomes in the GnomAD database, including 550 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.032 (306 hom., cov: 33)
  • Exomes 𝑓: 0.0034 (244 hom.)
• Consequence: PKD1 NM_001009944.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.733

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0021684766).
• BP6: Variant 16-2116537-G-A is Benign according to our data. Variant chr16-2116537-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 256927.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2116537-G-A is described in Lovd as [Benign]. Variant chr16-2116537-G-A is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.108 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PKD1	NM_001009944.3	c.1714C>T	p.Pro572Ser	missense_variant	8/46	ENST00000262304.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PKD1	ENST00000262304.9	c.1714C>T	p.Pro572Ser	missense_variant	8/46	1	NM_001009944.3	P5
PKD1	ENST00000423118.5	c.1714C>T	p.Pro572Ser	missense_variant	8/46	1		A2
PKD1	ENST00000488185.2	c.472+952C>T		intron_variant		5
PKD1	ENST00000568591.5	c.*42C>T		3_prime_UTR_variant, NMD_transcript_variant	4/12	2

Frequencies

GnomAD3 genomes AF: 0.0320 AC: 4873 AN: 152158 Hom.: 306 Cov.: 33

Gnomad AFR AF: 0.111

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0109

Gnomad ASJ AF: 0.000865

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000691

Gnomad OTH AF: 0.0263

GnomAD3 exomes AF: 0.00784 AC: 1316 AN: 167828 Hom.: 67 AF XY: 0.00557 AC XY: 509 AN XY: 91384

Gnomad AFR exome AF: 0.117

Gnomad AMR exome AF: 0.00677

Gnomad ASJ exome AF: 0.00104

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000124

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000382

Gnomad OTH exome AF: 0.00344

GnomAD4 exome AF: 0.00339 AC: 4676 AN: 1378130 Hom.: 244 Cov.: 29 AF XY: 0.00288 AC XY: 1970 AN XY: 683460

Gnomad4 AFR exome AF: 0.113

Gnomad4 AMR exome AF: 0.00748

Gnomad4 ASJ exome AF: 0.000912

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000150

Gnomad4 FIN exome AF: 0.0000244

Gnomad4 NFE exome AF: 0.000288

Gnomad4 OTH exome AF: 0.00822

GnomAD4 genome AF: 0.0320 AC: 4880 AN: 152276 Hom.: 306 Cov.: 33 AF XY: 0.0308 AC XY: 2293 AN XY: 74450

Gnomad4 AFR AF: 0.111

Gnomad4 AMR AF: 0.0109

Gnomad4 ASJ AF: 0.000865

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.0000941

Gnomad4 NFE AF: 0.000691

Gnomad4 OTH AF: 0.0260

Alfa AF: 0.00967 Hom.: 21

Bravo AF: 0.0364

ESP6500AA AF: 0.0981 AC: 422

ESP6500EA AF: 0.000474 AC: 4

ExAC AF: 0.00713 AC: 836

Asia WGS AF: 0.00520 AC: 18 AN: 3478

ClinVar

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

Polycystic kidney disease, adult type Benign:2

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	Jun 02, 2020	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 26, 2019	This variant is associated with the following publications: (PMID: 22383692, 22008521, 17574468, 11967008) -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Polycystic kidney disease Benign:1

Benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The PKD1 p.Pro572Ser variant was identified in 7 of 788 proband chromosomes (frequency: 0.009) from French, Spanish and North American individuals or families with ADPKD, occurring in the homozygous state in some probands (Bataille 2011, Rossetti 2002, Garcia-Gonzalez 2007, Rossetti 2012). The variant was also identified in dbSNP (ID: rs149022148) as “NA”, ADPKD Mutation Database (classification Likely Neutral), and COSMIC (in an adenocarcinoma- large intestine), and not in the Clinvitae, ClinVar, GeneInsight COGR, MutDB, PKD1-LOVD, and PKD1-LOVD 3.0 databases. The variant was identified in the 1000 Genomes Project in 204 of 5012 chromosomes (frequency: 0.0407), HAP-MAP populations: -AFR in 194 of 1322 chromosomes (frequency: 0.1467) and AMR in 10 of 694 chromosomes (frequency: 0.0144), NHLBI GO Exome Sequencing Project in 4 of 8440 (frequency: 0.0005) European American alleles and in 422 of 4300 African American alleles (frequency: 0.0981), and in the Exome Aggregation Consortium database (March 14 2016) in 382 of 18478 chromosomes (frequency 0.02) in the following populations: African in 360 (13 homozygous) of 1826 chromosomes (frequency: 0.1972), Latino in 16 of 680 chromosomes (frequency: 0.02353), Other in 1 of 174 chromosomes (frequency: 0006), European (Non-Finnish) in 4 of 6948 chromosomes (frequency: 0.0006), and South Asian in 1 of 8022 chromosomes (frequency: 0.0001), but was not seen in East Asian and Finnish populations, increasing the likelihood this could be a low frequency benign variant. The p.Pro572 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and 1 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In summary, based on the above information, this variant meets our laboratory criteria to be classified as benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.64	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	13
DANN	Benign	0.80
DEOGEN2	Benign	0.18	T;.
Eigen	Benign	-0.77
Eigen_PC	Benign	-0.85
FATHMM_MKL	Benign	0.054	N
LIST_S2	Benign	0.70	T;T
MetaRNN	Benign	0.0022	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.4	M;M
MutationTaster	Benign	1.0	P;P
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-0.70	N;N
REVEL	Benign	0.017
Sift	Benign	0.41	T;T
Sift4G	Benign	0.52	T;T
Polyphen		0.18	B;B
Vest4		0.43
MVP		0.61
ClinPred		0.0089	T
GERP RS		1.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.034
gMVP		0.55

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs149022148; hg19: chr16-2166538;