rs201238819

Positions:

• chr16-2104572-A-C
• chr16-2104572-A-G
• chr16-2104572-A-T

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_001009944.3(PKD1):​c.8087T>G​(p.Leu2696Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L2696P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0015 (0 hom., cov: 20)
  • Exomes 𝑓: 0.00041 (1 hom.)
  • Failed GnomAD Quality Control
• Consequence: PKD1 NM_001009944.3 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:2
• Conservation: PhyloP100: 0.659

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]

PKD1 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0077767074).
• BP6: Variant 16-2104572-A-C is Benign according to our data. Variant chr16-2104572-A-C is described in ClinVar as [Likely_benign]. Clinvar id is 433983.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-2104572-A-C is described in Lovd as [Likely_benign].
• BS2: High AC in GnomAd4 at 219 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PKD1	NM_001009944.3	c.8087T>G	p.Leu2696Arg	missense_variant	22/46	ENST00000262304.9	NP_001009944.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PKD1	ENST00000262304.9	c.8087T>G	p.Leu2696Arg	missense_variant	22/46	1	NM_001009944.3	ENSP00000262304.4

Frequencies

GnomAD3 genomes AF: 0.00150 AC: 218 AN: 145412 Hom.: 0 Cov.: 20

Gnomad AFR AF: 0.00187

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00389

Gnomad ASJ AF: 0.00178

Gnomad EAS AF: 0.000846

Gnomad SAS AF: 0.00133

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00100

Gnomad OTH AF: 0.00300

GnomAD3 exomes AF: 0.00108 AC: 184 AN: 170576 Hom.: 0 AF XY: 0.00112 AC XY: 103 AN XY: 92332

Gnomad AFR exome AF: 0.00167

Gnomad AMR exome AF: 0.00203

Gnomad ASJ exome AF: 0.00245

Gnomad EAS exome AF: 0.000145

Gnomad SAS exome AF: 0.000699

Gnomad FIN exome AF: 0.000160

Gnomad NFE exome AF: 0.000886

Gnomad OTH exome AF: 0.00194

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.000412 AC: 596 AN: 1447962 Hom.: 1 Cov.: 30 AF XY: 0.000417 AC XY: 300 AN XY: 720112

Gnomad4 AFR exome AF: 0.00145

Gnomad4 AMR exome AF: 0.00174

Gnomad4 ASJ exome AF: 0.000734

Gnomad4 EAS exome AF: 0.00134

Gnomad4 SAS exome AF: 0.000341

Gnomad4 FIN exome AF: 0.0000793

Gnomad4 NFE exome AF: 0.000301

Gnomad4 OTH exome AF: 0.000501

GnomAD4 genome AF: 0.00150 AC: 219 AN: 145524 Hom.: 0 Cov.: 20 AF XY: 0.00151 AC XY: 107 AN XY: 70886

Gnomad4 AFR AF: 0.00189

Gnomad4 AMR AF: 0.00388

Gnomad4 ASJ AF: 0.00178

Gnomad4 EAS AF: 0.000848

Gnomad4 SAS AF: 0.00133

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00100

Gnomad4 OTH AF: 0.00297

Alfa AF: 0.000692 Hom.: 0

ExAC AF: 0.000474 AC: 54

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

Submissions by phenotype

Polycystic kidney disease Benign:1

Benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The PKD1 p.Leu2696Arg variant was identified in 14 of 286 proband chromosomes (frequency: 0.049) from individuals or families with ADPKD, and was not identified in 100 control chromosomes from healthy individuals (Phakdeekitcharoen 2001, Bataille 2011, Yu 2011). The p.Leu2696Arg variant was identified in the dbSNP (ID: rs201238819) with no known clinical significance. The variant was not identified in NHLBI Exome Sequencing Project (Exome Variant Server). The variant was identified in Exome Aggregation Consortium (March 14, 2016), in 42 of 19230 chromosomes (frequency: 0.002) or 10 of 8070 South Asians, 24 of 7400 European (Non-Finnish), 2 of 628 Latino, 5 of 1616 African and 1 of 178 Other populations and not found in East Asian and European (Finnish), increasing the likelihood this could be a low frequency benign variant. The variant was identified in the PKD Mutation Database and was classified as likely neutral. The p.Leu2696 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. In a study of 41 Thai probands with ADPKD and pathogenic variants in the replicated portion of the PKD1 gene, the p.Leu2696Arg variant was identified to occur in non-conservative region within the REJ domain, but its effect on the three-dimensional structure is unknown. Glutamic acid and arginine are observed in the corresponding positions of Fugu and murine polycystin-1, respectively, suggesting a noncritical role for a nonpolar residue at this location (Phakdeekitcharoen 2001). In ADPKD family studies, the variant was identified in a fetus with cystic kidneys resembling ADPKD on ultrasound however it co-occurred with a de novo PKD1 “likely pathogenic” variant (c.9222C>G, p.Asn3074Lys. The fetus was also identified to carry a HNF1β “highly likely pathogenic” variant (c.883C>T, p.Arg295Cys) which was also identified in the father and paternal grandmother who had cystic kidneys consistent with the HNF1β phenotype. The PKD1 p.Leu2696Arg variant was inherited from the mother with a normal renal phenotype. (Bergmann_2011_22034641). 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 Benign. -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Aug 01, 2023

PKD1: BP4 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.043
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	4.7
DANN	Benign	0.57
DEOGEN2	Benign	0.13	T;.
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.28	N
LIST_S2	Benign	0.044	T;T
M_CAP	Benign	0.051	D
MetaRNN	Benign	0.0078	T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	-2.2	N;N
PrimateAI	Benign	0.43	T
PROVEAN	Benign	2.1	N;N
REVEL	Benign	0.25
Sift	Benign	0.89	T;T
Sift4G	Benign	0.93	T;T
Polyphen		0.0	B;B
Vest4		0.16
MVP		0.76
ClinPred		0.00030	T
GERP RS		-1.7
Varity_R		0.055
gMVP		0.16

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs201238819; hg19: chr16-2154573; COSMIC: COSV51910409; COSMIC: COSV51910409;