rs9936785

Positions:

• chr16-2105425-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001009944.3(PKD1):​c.7913A>G​(p.His2638Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0555 in 1,477,104 control chromosomes in the GnomAD database, including 8,441 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.18 (4065 hom., cov: 32)
  • Exomes 𝑓: 0.041 (4376 hom.)
• Consequence: PKD1 NM_001009944.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 3.35

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=0.010522425).
• BP6: Variant 16-2105425-T-C is Benign according to our data. Variant chr16-2105425-T-C is described in ClinVar as [Benign]. Clinvar id is 257008.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2105425-T-C is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.401 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PKD1	NM_001009944.3	c.7913A>G	p.His2638Arg	missense_variant	21/46	ENST00000262304.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PKD1	ENST00000262304.9	c.7913A>G	p.His2638Arg	missense_variant	21/46	1	NM_001009944.3	P5

Frequencies

GnomAD3 genomes AF: 0.181 AC: 27423 AN: 151594 Hom.: 4044 Cov.: 32

Gnomad AFR AF: 0.405

Gnomad AMI AF: 0.123

Gnomad AMR AF: 0.130

Gnomad ASJ AF: 0.158

Gnomad EAS AF: 0.00348

Gnomad SAS AF: 0.0275

Gnomad FIN AF: 0.0759

Gnomad MID AF: 0.183

Gnomad NFE AF: 0.0991

Gnomad OTH AF: 0.179

GnomAD3 exomes AF: 0.0440 AC: 9388 AN: 213374 Hom.: 1502 AF XY: 0.0383 AC XY: 4521 AN XY: 117948

Gnomad AFR exome AF: 0.297

Gnomad AMR exome AF: 0.0438

Gnomad ASJ exome AF: 0.0559

Gnomad EAS exome AF: 0.00240

Gnomad SAS exome AF: 0.0100

Gnomad FIN exome AF: 0.0127

Gnomad NFE exome AF: 0.0343

Gnomad OTH exome AF: 0.0578

GnomAD4 exome AF: 0.0411 AC: 54510 AN: 1325394 Hom.: 4376 Cov.: 33 AF XY: 0.0405 AC XY: 26842 AN XY: 663000

Gnomad4 AFR exome AF: 0.264

Gnomad4 AMR exome AF: 0.0501

Gnomad4 ASJ exome AF: 0.0937

Gnomad4 EAS exome AF: 0.00613

Gnomad4 SAS exome AF: 0.0189

Gnomad4 FIN exome AF: 0.0551

Gnomad4 NFE exome AF: 0.0352

Gnomad4 OTH exome AF: 0.0661

GnomAD4 genome AF: 0.181 AC: 27486 AN: 151710 Hom.: 4065 Cov.: 32 AF XY: 0.174 AC XY: 12879 AN XY: 74150

Gnomad4 AFR AF: 0.406

Gnomad4 AMR AF: 0.130

Gnomad4 ASJ AF: 0.158

Gnomad4 EAS AF: 0.00349

Gnomad4 SAS AF: 0.0275

Gnomad4 FIN AF: 0.0759

Gnomad4 NFE AF: 0.0992

Gnomad4 OTH AF: 0.177

Alfa AF: 0.133 Hom.: 440

Bravo AF: 0.199

ExAC AF: 0.0483 AC: 5488

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Polycystic kidney disease, adult type Benign:1

Benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Jul 07, 2020

- -

Polycystic kidney disease Benign:1

Benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The PKD1 p.His2638Arg variant was identified in 56 of 674 proband chromosomes (frequency: 0.083) from individuals or families with ADPKD or renal disease, and was not identified in 100 control chromosomes from healthy individuals (Bataille 2011, Bouba 2001, McCluskey 2002, Rossetti 2012). All the studies have identified the variant as a polymorphism. The p.His2638Arg variant was identified in the dbSNP (ID: rs9936785) with unknown clinical significance with a minor allele frequency 0.1356 (679 of 5007 chromosomes in 1000 Genome Project). The variant was identified in Exome Aggregation Consortium (ExAC) database (released March 14, 2016) in 4424 of 106234 chromosomes, 501 of which are homozygous (frequency: 0.04164) or 192 of 6148 of European (Finnish), 2099 of 57384 European (Non-Finnish), 177 of 10876 Latino, 1653 of 6824 African, 228 of 16016, South Asians, 33 of 790 Other and in 42 of 8196 East Asians chromosomes. The variant was identified in PKD Mutation Database and classified as “likely neutral”; and in GeneInsight the variant was identified by one submitter and classified as benign. In Clinvitae the variant was identified by EmyClass and identified as benign. The p.His2638 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. In addition this variant was identified co-occurring with a pathogenic PKD1 variant (PKD1, EXON43, c.11798_11810del, p.Leu3933ArgfsX8) in a patient with a clinical diagnosis of ADPKD. In summary, based on the above information, this variant meets our laboratory criteria to be classified as benign. -

Autosomal dominant polycystic kidney disease Benign:1

Benign, criteria provided, single submitter

research

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

Jan 01, 2019

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Dec 30, 2019

This variant is associated with the following publications: (PMID: 11571556, 22008521, 22383692) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.059
BayesDel_addAF	Benign	-0.65	T
BayesDel_noAF	Benign	-0.71
CADD	Benign	12
DANN	Benign	0.35
DEOGEN2	Benign	0.21	T;.
Eigen	Benign	-1.1
Eigen_PC	Benign	-0.92
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.16	T;T
MetaRNN	Benign	0.011	T;T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	0.0	N;N
MutationTaster	Benign	1.0	P;P
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-0.72	N;N
REVEL	Benign	0.10
Sift	Benign	0.37	T;T
Sift4G	Benign	0.17	T;T
Polyphen		0.0	B;B
Vest4		0.044
ClinPred		0.0044	T
GERP RS		2.5
Varity_R		0.040
gMVP		0.30

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: rs9936785; hg19: chr16-2155426; COSMIC: COSV51919516; COSMIC: COSV51919516;