chr16-2114489-A-G

Position:

• chr16-2114489-A-G

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PP3_Strong PP5_Very_Strong

The NM_001009944.3(PKD1):​c.2534T>C​(p.Leu845Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000485 in 1,444,302 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: PKD1 NM_001009944.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:13
• Conservation: PhyloP100: 8.09

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 Pathogenic. Variant got 12 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.961
• PP5: Variant 16-2114489-A-G is Pathogenic according to our data. Variant chr16-2114489-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 8206.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2114489-A-G is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PKD1	NM_001009944.3	c.2534T>C	p.Leu845Ser	missense_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.2534T>C	p.Leu845Ser	missense_variant	11/46	1	NM_001009944.3	ENSP00000262304	P5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000435 AC: 1 AN: 230128 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 127382

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000851

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000485 AC: 7 AN: 1444302 Hom.: 0 Cov.: 34 AF XY: 0.00000417 AC XY: 3 AN XY: 719042

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000258

Gnomad4 NFE exome AF: 0.00000540

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:13

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Polycystic kidney disease, adult type Pathogenic:6

Pathogenic, criteria provided, single submitter	clinical testing	Juno Genomics, Hangzhou Juno Genomics, Inc	Jul 19, 2024	PM2_Supporting+PS4_Moderate+PM6+PP1_Strong+PP4 -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	Feb 23, 2023	The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: <0.001%). Protein truncation variants are a common disease-causing mechanism. Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000008206). The variant has been previously reported as de novo in a similarly affected individual (PMID: 26139440). The variant has been observed in multiple (>3) similarly affected unrelated individuals (PMID: 10364515, 15772804, 22383692, 26139440). The variant has been reported to co-segregate with the disease in at least 7 similarly affected relatives/individuals in at least two unrelated families (PMID: 15772804, 22383692). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 31, 2018	- -
Likely pathogenic, criteria provided, single submitter	research	Cavalleri Lab, Royal College of Surgeons in Ireland	Feb 05, 2020	PS1, PP3, PP4 -
Likely pathogenic, criteria provided, single submitter	research	Molecular Biology Laboratory, Fundació Puigvert	Feb 01, 2020	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jul 01, 1999	- -

not provided Pathogenic:4

Likely pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics Laboratory, Skane University Hospital Lund	May 27, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Blueprint Genetics	Nov 20, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Nov 29, 2017	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Apr 18, 2024	In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 10854095, 22508176, 10364515, 25266109, 15772804, 23300259, 22383692, 26632257, 31740684, 30816285, 33454723, 36186434, 35783601, 33532864, 37909612, Durkie2023[paper], 38224954, 38541974, 26139440) -

Polycystic kidney disease Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The PKD1 p.Leu845Ser variant was identified in 4 of 346 proband chromosomes (frequency: 0.012) from individuals or families of Chinese and Finnish ethnicity with ADPKD and was not identified in 420 control chromosomes from healthy individuals (Audrezet 2015, Liu 2015, Peltola 2005, Thomas 1999). Thomas et al (1999) identified the p.Leu845Ser variant in one affected individual and was not identified in the patient’s unaffected daughter. The variant was also identified in dbSNP (ID: rs199476100) as “With Pathogenic allele”, ClinVar database as pathogenic by OMIM and in ADPKD Mutation Database as highly likely pathogenic. The variant was not identified in GeneInsight-COGR, LOVD 3.0, PKD1-LOVD, databases nor was it identified in the 1000 Genomes and the NHLBI GO Exome Sequencing Projects. The variant was identified in control databases in 1 of 226770 chromosomes at a frequency of 0.000004 (Genome Aggregation Consortium Feb 27, 2017). 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.Leu845Ser residue is conserved in mammals but not in more distantly related organisms and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the p.Leu845Ser variant may impact the protein. However, this information is not predictive enough to assume pathogenicity. The variant predicts a change from a neutral and hydrophobic Leu to a polar Ser at position 845, six residues N-terminal to the start of PKD domain 2 (Thomas 1999). The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. The variant is located within the Polycystin cation channel functional domain increasing the likelihood that it may have clinical significance. 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 pathogenic role for this variant. This variant is classified as likely pathogenic. -

PKD1-related disorder Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 26, 2024

The PKD1 c.2534T>C variant is predicted to result in the amino acid substitution p.Leu845Ser. This variant has been repeatedly reported in unrelated patients with autosomal dominant polycystic kidney disease (ADPKD) and it was widely documented as a “highly likely pathogenic” variant (Thomas et al. 1999. PubMed ID: 10364515; Liu et al. 2015. PubMed ID: 26632257; Peltola et al. 2005. PubMed ID: 15772804; http://pkdb.mayo.edu). This variant is reported in 0.0085% of alleles in individuals of European (Finnish) descent in gnomAD. This variant is interpreted as pathogenic. -

Polycystic kidney disease 3 with or without polycystic liver disease Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Molecular Diagnostics Laboratory, M Health Fairview: University of Minnesota

Mar 28, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.80
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.23
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.70	D;.
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.44	T;T
M_CAP	Pathogenic	0.93	D
MetaRNN	Pathogenic	0.96	D;D
MetaSVM	Benign	-0.33	T
MutationAssessor	Uncertain	2.6	M;M
MutationTaster	Benign	1.0	A;A
PrimateAI	Benign	0.45	T
PROVEAN	Uncertain	-3.4	D;D
REVEL	Uncertain	0.53
Sift	Uncertain	0.0010	D;D
Sift4G	Uncertain	0.0070	D;D
Polyphen		1.0	D;D
Vest4		0.89
MutPred		0.70		Gain of disorder (P = 0.0106);Gain of disorder (P = 0.0106);
MVP		0.98
ClinPred		0.88	D
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.52
gMVP		0.91

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: rs199476100; hg19: chr16-2164490;