16-2109849-G-A

Position:

• chr16-2109849-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001009944.3(PKD1):​c.5318C>T​(p.Thr1773Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00176 in 1,610,698 control chromosomes in the GnomAD database, including 25 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0010 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0018 (24 hom.)
• Consequence: PKD1 NM_001009944.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 0.357

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=0.011328936).
• BP6: Variant 16-2109849-G-A is Benign according to our data. Variant chr16-2109849-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 433966.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2109849-G-A is described in Lovd as [Benign]. Variant chr16-2109849-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00101 (154/152368) while in subpopulation SAS AF= 0.0139 (67/4828). AF 95% confidence interval is 0.0112. There are 1 homozygotes in gnomad4. There are 97 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 154 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PKD1	NM_001009944.3	c.5318C>T	p.Thr1773Ile	missense_variant	15/46	ENST00000262304.9	NP_001009944.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PKD1	ENST00000262304.9	c.5318C>T	p.Thr1773Ile	missense_variant	15/46	1	NM_001009944.3	ENSP00000262304	P5

Frequencies

GnomAD3 genomes AF: 0.00101 AC: 154 AN: 152250 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000217

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.0139

Gnomad FIN AF: 0.000377

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000999

Gnomad OTH AF: 0.000955

GnomAD3 exomes AF: 0.00226 AC: 564 AN: 249112 Hom.: 6 AF XY: 0.00302 AC XY: 408 AN XY: 135314

Gnomad AFR exome AF: 0.0000623

Gnomad AMR exome AF: 0.000318

Gnomad ASJ exome AF: 0.000100

Gnomad EAS exome AF: 0.0000545

Gnomad SAS exome AF: 0.0141

Gnomad FIN exome AF: 0.0000463

Gnomad NFE exome AF: 0.000992

Gnomad OTH exome AF: 0.00115

GnomAD4 exome AF: 0.00184 AC: 2686 AN: 1458330 Hom.: 24 Cov.: 34 AF XY: 0.00228 AC XY: 1651 AN XY: 725454

Gnomad4 AFR exome AF: 0.000150

Gnomad4 AMR exome AF: 0.000336

Gnomad4 ASJ exome AF: 0.000268

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0140

Gnomad4 FIN exome AF: 0.000115

Gnomad4 NFE exome AF: 0.00123

Gnomad4 OTH exome AF: 0.00131

GnomAD4 genome AF: 0.00101 AC: 154 AN: 152368 Hom.: 1 Cov.: 33 AF XY: 0.00130 AC XY: 97 AN XY: 74500

Gnomad4 AFR AF: 0.000216

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.0139

Gnomad4 FIN AF: 0.000377

Gnomad4 NFE AF: 0.000999

Gnomad4 OTH AF: 0.000945

Alfa AF: 0.00101 Hom.: 0

Bravo AF: 0.000612

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00105 AC: 9

ExAC AF: 0.00241 AC: 291

EpiCase AF: 0.000927

EpiControl AF: 0.00107

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

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 03, 2021	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	Dec 19, 2022	- -

Polycystic kidney disease, adult type Benign:2

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Dec 19, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Apr 12, 2022	- -

Polycystic kidney disease Benign:1

Benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The PKD1 p.Thr1773Ile variant was not identified in the literature nor was it identified in the Clinvitae, ClinVar, MutDB, PKD1-LOVD and PKD1-LOVD 3.0 databases. The variant was identified in dbSNP (ID: rs140162759) as “NA” with a mean allele frequency of 0.0018 (9 of 5000 chromosomes) in the 1000 Genomes Project; NHLBI GO Exome Sequencing Project in 9 of 8588 European American alleles and not found in African Americans, the Exome Aggregation Consortium database (March 14, 2016) in 290 (3 homozygous) of 118260 chromosomes (freq. 0.002452) in the following populations: South Asian in 234 of 16450 chromosomes (freq. 0.01422), European (Non-Finnish) in 51 of 64804 chromosomes (freq. 0.000787), Latino in 3 of 11454 chromosomes (freq. 0.0002619), African in 1 of 10028 chromosomes (freq. 0.00009972 and Other in 1 of 862 chromosomes (freq. 0.00116), but was not seen in East Asian and Finnish populations, increasing the likelihood this could be a low frequency benign variant. 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 variant was identified in GeneInsight COGR (benign) and the ADPKD Mutation Database (likely neutral). The p.Thr1773 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 amino acid Isoleucine is present in Ciona intestinalis, increasing the likelihood that this variant does not have clinical significance. 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 is classified as benign. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Nov 01, 2023

PKD1: BP4, BS1, BS2 -

PKD1-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 07, 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
AlphaMissense	Benign	0.092
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	0.35
DANN	Benign	0.95
DEOGEN2	Benign	0.24	T;.
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.080	N
LIST_S2	Benign	0.16	T;T
MetaRNN	Benign	0.011	T;T
MetaSVM	Benign	-0.89	T
MutationAssessor	Benign	1.1	L;L
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-1.8	N;N
REVEL	Benign	0.11
Sift	Benign	0.15	T;T
Sift4G	Uncertain	0.0060	D;D
Polyphen		0.43	B;B
Vest4		0.19
MVP		0.49
ClinPred		0.012	T
GERP RS		-2.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.022
gMVP		0.53

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: rs140162759; hg19: chr16-2159850;