16-2102849-A-G

Position:

• chr16-2102849-A-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001009944.3(PKD1):​c.8913T>C​(p.Ala2971Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00547 in 1,594,920 control chromosomes in the GnomAD database, including 450 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.032 (241 hom., cov: 32)
  • Exomes 𝑓: 0.0029 (209 hom.)
• Consequence: PKD1 NM_001009944.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -1.96

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BP6: Variant 16-2102849-A-G is Benign according to our data. Variant chr16-2102849-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 257031.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2102849-A-G is described in Lovd as [Benign]. Variant chr16-2102849-A-G is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-1.96 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.108 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PKD1	NM_001009944.3	c.8913T>C	p.Ala2971Ala	synonymous_variant	24/46	ENST00000262304.9	NP_001009944.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PKD1	ENST00000262304.9	c.8913T>C	p.Ala2971Ala	synonymous_variant	24/46	1	NM_001009944.3	ENSP00000262304.4

Frequencies

GnomAD3 genomes AF: 0.0319 AC: 4444 AN: 139172 Hom.: 242 Cov.: 32

Gnomad AFR AF: 0.111

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0111

Gnomad ASJ AF: 0.000932

Gnomad EAS AF: 0.00107

Gnomad SAS AF: 0.000236

Gnomad FIN AF: 0.000101

Gnomad MID AF: 0.00680

Gnomad NFE AF: 0.000812

Gnomad OTH AF: 0.0299

GnomAD3 exomes AF: 0.00775 AC: 1928 AN: 248664 Hom.: 98 AF XY: 0.00559 AC XY: 755 AN XY: 135054

Gnomad AFR exome AF: 0.102

Gnomad AMR exome AF: 0.00660

Gnomad ASJ exome AF: 0.000902

Gnomad EAS exome AF: 0.000163

Gnomad SAS exome AF: 0.000229

Gnomad FIN exome AF: 0.0000472

Gnomad NFE exome AF: 0.000420

Gnomad OTH exome AF: 0.00279

GnomAD4 exome AF: 0.00293 AC: 4262 AN: 1455626 Hom.: 209 Cov.: 34 AF XY: 0.00248 AC XY: 1798 AN XY: 724176

Gnomad4 AFR exome AF: 0.0964

Gnomad4 AMR exome AF: 0.00738

Gnomad4 ASJ exome AF: 0.000804

Gnomad4 EAS exome AF: 0.000227

Gnomad4 SAS exome AF: 0.000244

Gnomad4 FIN exome AF: 0.0000387

Gnomad4 NFE exome AF: 0.000260

Gnomad4 OTH exome AF: 0.00708

GnomAD4 genome AF: 0.0320 AC: 4458 AN: 139294 Hom.: 241 Cov.: 32 AF XY: 0.0308 AC XY: 2089 AN XY: 67908

Gnomad4 AFR AF: 0.111

Gnomad4 AMR AF: 0.0111

Gnomad4 ASJ AF: 0.000932

Gnomad4 EAS AF: 0.00108

Gnomad4 SAS AF: 0.000237

Gnomad4 FIN AF: 0.000101

Gnomad4 NFE AF: 0.000812

Gnomad4 OTH AF: 0.0294

Alfa AF: 0.00818 Hom.: 15

Bravo AF: 0.0336

EpiCase AF: 0.000654

EpiControl AF: 0.000593

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

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

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Oct 09, 2017	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	May 11, 2021	This variant is associated with the following publications: (PMID: 9285784, 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.Ala2971Ala variant was identified in 5 of 698 proband chromosomes (frequency: 0.007) from individuals or families with ADPKD, and was not identified in 442 control chromosomes from healthy individuals (Bataille_2011, Garcia-Gonzalez_2007, Rossetti_2012). The variant was also identified in dbSNP (ID: rs9926309) “With NA allele”, in 1000 Genomes Project in 190 of 5013 chromosomes (frequency: 0.0379), and in the NHLBI GO Exome Sequencing Project (ESP) in 5 of 8580 European American and in 394 of 4390 African American alleles. In addition, the variant is identified in the Exome Aggregation Consortium database (March 14, 2016) in 1155 of 119736 chromosomes (freq. 0.01) in the following populations: African in 1053 (57 homozygous) of 10158 chromosomes (freq. 0.1037), other in 5 of 886 chromosomes (freq. 0.006), Latino in 65 of 11538 chromosomes (freq. 0.006), European (Non-Finnish) in 29 of 65418 chromosomes (freq. 0.0004), South Asian in 2 of 16504 chromosomes (freq. 0.0001), East Asian in 1 of 6610 chromosomes (freq. 0.0001) but was not seen in a Finish population, increasing the likelihood this could be a low frequency benign variant. The variant is also listed in GeneInsight COGR (classified as benign), and in ADPKD Mutation Database (6x as likely neutral). The p.Ala2971Ala variant is not expected to have clinical significance because it does not result in a change of amino acid and is not located in a known consensus splice site. In addition, 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
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.071
DANN	Benign	0.41

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: rs9926309; hg19: chr16-2152850;