rs376283361

chr16-2106458-G-A

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM5 BP4 BP6 BS2

The NM_001009944.3(PKD1):c.7429C>T(p.Arg2477Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000768 in 1,590,394 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R2477H) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00063 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00078 (3 hom.)
• Consequence: PKD1 NM_001009944.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:3
• Conservation: PhyloP100: 1.94

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 Likely_benign. Variant got -4 ACMG points.

• PM5: Other missense variant is known to change same aminoacid residue: Variant chr16-2106456-GCG-GACTGT is described in Lovd as [Pathogenic].
• BP4: Computational evidence support a benign effect (MetaRNN=0.27638018).
• BP6: Variant 16-2106458-G-A is Benign according to our data. Variant chr16-2106458-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 257000.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=2}. Variant chr16-2106458-G-A is described in Lovd as [Likely_benign].
• BS2: High AC in GnomAd at 96 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PKD1	NM_001009944.3	c.7429C>T	p.Arg2477Cys	missense_variant	18/46	ENST00000262304.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PKD1	ENST00000262304.9	c.7429C>T	p.Arg2477Cys	missense_variant	18/46	1	NM_001009944.3	P5

Frequencies

GnomAD3 genomes AF: 0.000631 AC: 96 AN: 152196 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00207

Gnomad FIN AF: 0.00179

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000823

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.00118 AC: 220 AN: 186738 Hom.: 0 AF XY: 0.00142 AC XY: 147 AN XY: 103476

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000337

Gnomad ASJ exome AF: 0.00224

Gnomad EAS exome AF: 0.0000691

Gnomad SAS exome AF: 0.00314

Gnomad FIN exome AF: 0.00222

Gnomad NFE exome AF: 0.000995

Gnomad OTH exome AF: 0.000404

GnomAD4 exome AF: 0.000783 AC: 1126 AN: 1438080 Hom.: 3 Cov.: 33 AF XY: 0.000870 AC XY: 622 AN XY: 715086

Gnomad4 AFR exome AF: 0.0000302

Gnomad4 AMR exome AF: 0.000277

Gnomad4 ASJ exome AF: 0.00170

Gnomad4 EAS exome AF: 0.0000511

Gnomad4 SAS exome AF: 0.00307

Gnomad4 FIN exome AF: 0.00289

Gnomad4 NFE exome AF: 0.000546

Gnomad4 OTH exome AF: 0.00112

GnomAD4 genome AF: 0.000630 AC: 96 AN: 152314 Hom.: 0 Cov.: 32 AF XY: 0.000618 AC XY: 46 AN XY: 74490

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.000261

Gnomad4 ASJ AF: 0.00144

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00207

Gnomad4 FIN AF: 0.00179

Gnomad4 NFE AF: 0.000823

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.00110 Hom.: 0

Bravo AF: 0.000499

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000463 AC: 3

ExAC AF: 0.00109 AC: 124

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2 Benign:2

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Uncertain significance, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The PKD1 p.R2477C variant was identified in a family with polycystickidney disease along with an F3168L variant, however only the F3168L variant segregated with disease (Rossetti_2007_PMID:17582161). The variant was also identified in dbSNP (ID: rs376283361), ClinVar (classified as a VUS by GeneDx and Centre for Mendelian Genomics, University Medical Centre Ljubljana and as likely benign by Prevention Genetics), LOVD 3.0 (classified as likely benign) and the ADPKD Mutation Database (classified as likely neutral). The variant was identified in control databases in 248 of 218070 chromosomes at a frequency of 0.001137 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: South Asian in 83 of 26454 chromosomes (freq: 0.003138), European (Finnish) in 31 of 13408 chromosomes (freq: 0.002312), Ashkenazi Jewish in 21 of 9226 chromosomes (freq: 0.002276), European (non-Finnish) in 97 of 97806 chromosomes (freq: 0.000992), Other in 5 of 6038 chromosomes (freq: 0.000828), Latino in 10 of 30478 chromosomes (freq: 0.000328) and East Asian in 1 of 16028 chromosomes (freq: 0.000062), but was not observed in the African population. The p.Arg2477 residue is conserved in mammals and three of four computational analyses (SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; 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) 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. This variant is classified as a variant of uncertain significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Oct 08, 2015	The R2477C variant in the PKD1 gene has been reported previously in an individual with polycystic kidney disease. However, this individual reportedly carried a second missense variant in the PKD1 gene that segregated with the disease, while the R2477C variant reportedly did not segregate with the disease (Rossetti et al., 2007). The R2477C variant was not observed at any significant frequency in approximately 4,800 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The R2477C variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is not conserved. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. A missense variant in the same residue (R2477H) has been reported in association with polycystic kidney disease type 1 (Chang et al., 2013), supporting the functional importance of this residue. We interpret R2477C as a variant of uncertain significance. -

Clubfoot;C0022680:Polycystic kidney disease;C0426790:Narrow chest;C3275899:Hyperechogenic kidneys Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Jan 01, 2017

- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.22
Cadd	Uncertain	25
Dann	Uncertain	1.0
DEOGEN2	Benign	0.30	T;.
Eigen	Uncertain	0.36
Eigen_PC	Uncertain	0.29
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.92	D;D
M_CAP	Pathogenic	0.97	D
MetaRNN	Benign	0.28	T;T
MetaSVM	Benign	-0.44	T
MutationAssessor	Uncertain	2.3	M;M
MutationTaster	Benign	0.93	D;D
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-2.2	N;N
REVEL	Uncertain	0.50
Sift	Benign	0.079	T;T
Sift4G	Uncertain	0.0060	D;D
Polyphen		1.0	D;D
Vest4		0.53
MVP		0.92
ClinPred		0.044	T
GERP RS		4.8
Varity_R		0.087
gMVP		0.49

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: rs376283361; hg19: chr16-2156459;