16-2106152-C-G

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_001009944.3(PKD1):c.7642G>C(p.Glu2548Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00575 in 1,607,232 control chromosomes in the GnomAD database, including 489 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.030 (258 hom., cov: 32)
  • Exomes 𝑓: 0.0032 (231 hom.)
• Consequence: PKD1 NM_001009944.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -2.74

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 -16 ACMG points.

• BP6: Variant 16-2106152-C-G is Benign according to our data. Variant chr16-2106152-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 257002.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2106152-C-G is described in Lovd as [Benign]. Variant chr16-2106152-C-G is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.1 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PKD1	NM_001009944.3	c.7642G>C	p.Glu2548Gln	missense_variant	19/46	ENST00000262304.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PKD1	ENST00000262304.9	c.7642G>C	p.Glu2548Gln	missense_variant	19/46	1	NM_001009944.3	P5

Frequencies

GnomAD3 genomes AF: 0.0298 AC: 4527 AN: 152078 Hom.: 258 Cov.: 32

Gnomad AFR AF: 0.103

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0102

Gnomad ASJ AF: 0.000864

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000691

Gnomad OTH AF: 0.0268

GnomAD3 exomes AF: 0.00674 AC: 1414 AN: 209726 Hom.: 75 AF XY: 0.00498 AC XY: 576 AN XY: 115646

Gnomad AFR exome AF: 0.108

Gnomad AMR exome AF: 0.00614

Gnomad ASJ exome AF: 0.00108

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000702

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000384

Gnomad OTH exome AF: 0.00227

GnomAD4 exome AF: 0.00323 AC: 4703 AN: 1455036 Hom.: 231 Cov.: 33 AF XY: 0.00274 AC XY: 1986 AN XY: 723782

Gnomad4 AFR exome AF: 0.107

Gnomad4 AMR exome AF: 0.00708

Gnomad4 ASJ exome AF: 0.000883

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000116

Gnomad4 FIN exome AF: 0.0000386

Gnomad4 NFE exome AF: 0.000295

Gnomad4 OTH exome AF: 0.00766

GnomAD4 genome AF: 0.0298 AC: 4536 AN: 152196 Hom.: 258 Cov.: 32 AF XY: 0.0285 AC XY: 2122 AN XY: 74428

Gnomad4 AFR AF: 0.103

Gnomad4 AMR AF: 0.0102

Gnomad4 ASJ AF: 0.000864

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.0000941

Gnomad4 NFE AF: 0.000691

Gnomad4 OTH AF: 0.0265

Alfa AF: 0.00193 Hom.: 3

Bravo AF: 0.0340

ESP6500AA AF: 0.0750 AC: 303

ESP6500EA AF: 0.000246 AC: 2

ExAC AF: 0.00709 AC: 834

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Oct 12, 2017	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 26, 2019	This variant is associated with the following publications: (PMID: 10577909, 17574468, 22008521, 22383692) -

Polycystic kidney disease, adult type Benign:1

Benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Jun 02, 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.Glu2548Gln variant was identified in 3 of 604 proband chromosomes (frequency: 0.005) from individuals or families with AKPKD, and was not identified in 200 control chromosomes from healthy individuals (Bataille_2011, Rossetti_2012, Watnick_1999). The variant was also identified in dbSNP (ID: rs rs28369051) with no allele association indicated and listed in 1000 Genomes Project in 192 of 5013 chromosomes (frequency: 0.0383), in NHLBI GO Exome Sequencing Project (ESP) in 2 of 8130 European American (frequency: 0.0002) and 303 in 4042 African American alleles (frequency: 0.075). The variant is also identified in The Exome Aggregation Consortium (ExAC) database (released Mar 14, 2016) in 541 of 500090 chromosomes (frequency: 0.011) of which 30 homozygotes are of African ethnicity increasing the likelihood that this may be a low frequency benign variant in certain populations of origin. Furthermore, the variant is listed in GeneInsight COGR database by LMM 1x as benign, in MutDB 1x as a polymorphism, and in ARPKD database 6x as likely neutral. The p. Glu2548residue 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. Furthermore, the variant amino acid (Gln) is present in dog, increasing the likelihood that this variant does not have clinical significance. 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, this variant meets our laboratory criteria to be classified as benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.45
Cadd	Benign	3.5
Dann	Benign	0.66
DEOGEN2	Benign	0.14	T;.
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.024	N
LIST_S2	Benign	0.64	T;T
MetaRNN	Benign	0.0020	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.49	N;N
MutationTaster	Benign	1.0	P;P
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-0.39	N;N
REVEL	Benign	0.060
Sift	Benign	0.57	T;T
Sift4G	Benign	0.58	T;T
Polyphen		0.053	B;B
Vest4		0.14
MVP		0.80
ClinPred		0.00044	T
GERP RS		-4.0
Varity_R		0.059
gMVP		0.37

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.22		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.22		Position offset: -2

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

Publications

LitVar

Other links and lift over

dbSNP: rs28369051; hg19: chr16-2156153;