16-2106248-G-C

Variant names:

• chr16-2106248-G-C
• rs797044902
• NM_001009944.3:c.7546C>G

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM2 PM5 PP3_Strong

The NM_001009944.3(PKD1):​c.7546C>G​(p.Arg2516Gly) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R2516H) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PKD1 NM_001009944.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 6.00
• Publications: 1 publications found

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 Gene-Disease associations (from GenCC):

• autosomal dominant polycystic kidney disease

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• polycystic kidney disease 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Laboratory for Molecular Medicine, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• autosomal recessive polycystic kidney disease

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• Caroli disease

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp

ACMG classification

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr16-2106247-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 3892035.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.961

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001009944.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PKD1	NM_001009944.3	MANE Select	c.7546C>G	p.Arg2516Gly	missense	Exon 19 of 46	NP_001009944.3
	PKD1	NM_000296.4		c.7546C>G	p.Arg2516Gly	missense	Exon 19 of 46	NP_000287.4

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PKD1	ENST00000262304.9	TSL:1 MANE Select	c.7546C>G	p.Arg2516Gly	missense	Exon 19 of 46	ENSP00000262304.4
	PKD1	ENST00000423118.5	TSL:1	c.7546C>G	p.Arg2516Gly	missense	Exon 19 of 46	ENSP00000399501.1
	PKD1	ENST00000415938.7	TSL:5	n.791C>G		non_coding_transcript_exon	Exon 5 of 17

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Polycystic kidney disease, adult type Uncertain:2

Dec 12, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jan 24, 2019

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The PKD1 c.7546C>G; p.Arg2516Gly variant (rs797044902), to our knowledge, is not reported in the medical literature or gene specific databases. This variant is also absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. The arginine at codon 2516 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Additional, another variant at this codon (p.Arg2516Cys) is reported in multiple individuals with autosomal dominant polycystic kidney disease and is considered likely pathogenic (Cornec-Le Gall 2013, Garcia-Gonzalez 2007, Rossetti 2007). However, given the lack of clinical and functional data, the significance of the p.Arg2516Gly variant is uncertain at this time. References: Cornec-Le Gall E et al. Type of PKD1 mutation influences renal outcome in ADPKD. J Am Soc Nephrol. 2013 May;24(6):1006-13. Garcia-Gonzalez MA et al. Evaluating the clinical utility of a molecular genetic test for polycystic kidney disease. Mol Genet Metab. 2007 Sep-Oct;92(1-2):160-7. Rossetti S et al. Comprehensive molecular diagnostics in autosomal dominant polycystic kidney disease. J Am Soc Nephrol. 2007 Jul;18(7):2143-60.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.62
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.20
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.52	D
Eigen	Pathogenic	0.72
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.81	T
M_CAP	Pathogenic	0.97	D
MetaRNN	Pathogenic	0.96	D
MetaSVM	Uncertain	0.036	D
MutationAssessor	Uncertain	2.7	M
PhyloP100		6.0
PrimateAI	Uncertain	0.74	T
PROVEAN	Uncertain	-3.4	D
REVEL	Pathogenic	0.71
Sift	Uncertain	0.012	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.88
MutPred		0.78		Loss of stability (P = 0.089)
MVP		0.92
ClinPred		0.99	D
GERP RS		5.0
Varity_R		0.52
gMVP		0.76
Mutation Taster		=2/98	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs797044902; hg19: chr16-2156249;