rs147350387

chr16-2104536-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.8123C>T(p.Thr2708Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0154 in 1,573,306 control chromosomes in the GnomAD database, including 229 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.011 (19 hom., cov: 20)
  • Exomes 𝑓: 0.016 (210 hom.)
• Consequence: PKD1 NM_001009944.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 9.37

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=0.011215836).
• BP6: Variant 16-2104536-G-A is Benign according to our data. Variant chr16-2104536-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 257011.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2104536-G-A is described in Lovd as [Likely_pathogenic]. Variant chr16-2104536-G-A is described in Lovd as [Benign]. Variant chr16-2104536-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0114 (1709/150234) while in subpopulation NFE AF= 0.0188 (1268/67612). AF 95% confidence interval is 0.0179. There are 19 homozygotes in gnomad4. There are 755 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 1710 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PKD1	NM_001009944.3	c.8123C>T	p.Thr2708Met	missense_variant	22/46	ENST00000262304.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PKD1	ENST00000262304.9	c.8123C>T	p.Thr2708Met	missense_variant	22/46	1	NM_001009944.3	P5

Frequencies

GnomAD3 genomes AF: 0.0114 AC: 1710 AN: 150116 Hom.: 19 Cov.: 20

Gnomad AFR AF: 0.00300

Gnomad AMI AF: 0.00220

Gnomad AMR AF: 0.0107

Gnomad ASJ AF: 0.00434

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00106

Gnomad FIN AF: 0.0112

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0188

Gnomad OTH AF: 0.00869

GnomAD3 exomes AF: 0.00968 AC: 1474 AN: 152302 Hom.: 11 AF XY: 0.00986 AC XY: 809 AN XY: 82088

Gnomad AFR exome AF: 0.00243

Gnomad AMR exome AF: 0.00704

Gnomad ASJ exome AF: 0.00453

Gnomad EAS exome AF: 0.000338

Gnomad SAS exome AF: 0.00113

Gnomad FIN exome AF: 0.0109

Gnomad NFE exome AF: 0.0174

Gnomad OTH exome AF: 0.00919

GnomAD4 exome AF: 0.0158 AC: 22553 AN: 1423072 Hom.: 210 Cov.: 30 AF XY: 0.0155 AC XY: 10936 AN XY: 706240

Gnomad4 AFR exome AF: 0.00299

Gnomad4 AMR exome AF: 0.00655

Gnomad4 ASJ exome AF: 0.00454

Gnomad4 EAS exome AF: 0.000207

Gnomad4 SAS exome AF: 0.00133

Gnomad4 FIN exome AF: 0.0138

Gnomad4 NFE exome AF: 0.0188

Gnomad4 OTH exome AF: 0.0133

GnomAD4 genome AF: 0.0114 AC: 1709 AN: 150234 Hom.: 19 Cov.: 20 AF XY: 0.0103 AC XY: 755 AN XY: 73348

Gnomad4 AFR AF: 0.00299

Gnomad4 AMR AF: 0.0107

Gnomad4 ASJ AF: 0.00434

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00106

Gnomad4 FIN AF: 0.0112

Gnomad4 NFE AF: 0.0188

Gnomad4 OTH AF: 0.00860

Alfa AF: 0.0148 Hom.: 7

Bravo AF: 0.0104

ESP6500AA AF: 0.00269 AC: 11

ESP6500EA AF: 0.0158 AC: 129

ExAC AF: 0.00428 AC: 462

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2024	PKD1: BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 11, 2020	This variant is associated with the following publications: (PMID: 27499327, 24374109) -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jul 17, 2018	- -

Polycystic kidney disease, adult type Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Apr 07, 2022	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Feb 20, 2020	- -

not specified Benign:1

Benign, no assertion criteria provided

clinical testing

Genome Diagnostics Laboratory, University Medical Center Utrecht

-

- -

PKD1-related condition Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 09, 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). -

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.Thr2708Met variant was identified in 10 of 1016 proband chromosomes (frequency: 0.01) from individuals or families with ADPKD (classified as a polymorphism) and was not identified in 100 control chromosomes from healthy individuals (Bataille 2011, Garcia-Gonzalez 2007, Rossetti 2001, Rossetti 2012). This variant has been seen in one individual from our laboratory as co-occurring with a pathogenic variant increasing the likelihood it may not have clinical significance. The variant was also identified in dbSNP (ID: rs147350387) as “N/A”. The variant was identified in the 1000 Genomes Project in 20 of 5000 chromosomes (frequency: 0.004); in NHLBI GO Exome Sequencing Project in 129 of 8168 European American (frequency: 0.016) and 11 of 4082 African American (frequency: 0.0027) alleles. In the Exome Aggregation Consortium database (March 14, 2016) in 114 of 17104 chromosomes of which 1 was homozygous (frequency: 0.00666) in the following populations: 101 of 6264 European (Non-Finnish) – frequency 0.01612; 6 of 7956 South Asian- frequency 0.0007541; 3 of 490 Latinos- frequency 0.006122; 2 of 60 Finnish - frequency 0.03333; 1 of 1246 African - frequency 0.0008026 and 1 of 164 Other- frequency: 0.006098) alleles. The variant was identified in ADPKD Mutation Database classified as likely neutral. The p.Thr2708 residue is conserved across mammals and other organisms, and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. 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. 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. -

Autosomal dominant polycystic kidney disease Benign:1

Likely benign, criteria provided, single submitter

research

Molecular Genetics of Inherited Kidney Disorders Laboratory, Garvan Institute of Medical Research

Jan 01, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.29
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.14
Cadd	Benign	22
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.73	D;.
Eigen	Uncertain	0.47
Eigen_PC	Uncertain	0.33
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.89	D;D
MetaRNN	Benign	0.011	T;T
MetaSVM	Benign	-0.63	T
MutationAssessor	Uncertain	2.8	M;M
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.59	T
PROVEAN	Uncertain	-3.4	D;D
REVEL	Uncertain	0.39
Sift	Uncertain	0.0010	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;D
Vest4		0.59
MVP		0.78
ClinPred		0.016	T
GERP RS		4.2
Varity_R		0.40
gMVP		0.71

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: rs147350387; hg19: chr16-2154537; COSMIC: COSV99032379; COSMIC: COSV99032379;