chr16-2114329-T-G

Variant names:

• chr16-2114329-T-G
• rs142357713
• NM_001009944.3:c.2694A>C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001009944.3(PKD1):​c.2694A>C​(p.Ala898Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0198 in 1,610,450 control chromosomes in the GnomAD database, including 380 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.013 (25 hom., cov: 32)
  • Exomes 𝑓: 0.020 (355 hom.)
• Consequence: PKD1 NM_001009944.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -1.13

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant 16-2114329-T-G is Benign according to our data. Variant chr16-2114329-T-G is described in ClinVar as [Benign]. Clinvar id is 256935.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2114329-T-G is described in Lovd as [Benign]. Variant chr16-2114329-T-G is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-1.13 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0132 (2017/152316) while in subpopulation NFE AF= 0.022 (1493/68018). AF 95% confidence interval is 0.021. There are 25 homozygotes in gnomad4. There are 935 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 2017 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PKD1	NM_001009944.3	c.2694A>C	p.Ala898Ala	synonymous_variant	Exon 11 of 46	ENST00000262304.9	NP_001009944.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PKD1	ENST00000262304.9	c.2694A>C	p.Ala898Ala	synonymous_variant	Exon 11 of 46	1	NM_001009944.3	ENSP00000262304.4

Frequencies

GnomAD3 genomes AF: 0.0133 AC: 2017 AN: 152198 Hom.: 25 Cov.: 32

Gnomad AFR AF: 0.00367

Gnomad AMI AF: 0.0164

Gnomad AMR AF: 0.00870

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00373

Gnomad FIN AF: 0.0165

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0219

Gnomad OTH AF: 0.0115

GnomAD3 exomes AF: 0.0130 AC: 3211 AN: 247924 Hom.: 34 AF XY: 0.0129 AC XY: 1741 AN XY: 134848

Gnomad AFR exome AF: 0.00375

Gnomad AMR exome AF: 0.00681

Gnomad ASJ exome AF: 0.00322

Gnomad EAS exome AF: 0.0000545

Gnomad SAS exome AF: 0.00275

Gnomad FIN exome AF: 0.0164

Gnomad NFE exome AF: 0.0213

Gnomad OTH exome AF: 0.0135

GnomAD4 exome AF: 0.0205 AC: 29858 AN: 1458134 Hom.: 355 Cov.: 34 AF XY: 0.0201 AC XY: 14581 AN XY: 725394

Gnomad4 AFR exome AF: 0.00341

Gnomad4 AMR exome AF: 0.00689

Gnomad4 ASJ exome AF: 0.00299

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.00277

Gnomad4 FIN exome AF: 0.0171

Gnomad4 NFE exome AF: 0.0243

Gnomad4 OTH exome AF: 0.0197

GnomAD4 genome AF: 0.0132 AC: 2017 AN: 152316 Hom.: 25 Cov.: 32 AF XY: 0.0126 AC XY: 935 AN XY: 74490

Gnomad4 AFR AF: 0.00366

Gnomad4 AMR AF: 0.00869

Gnomad4 ASJ AF: 0.00202

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00373

Gnomad4 FIN AF: 0.0165

Gnomad4 NFE AF: 0.0220

Gnomad4 OTH AF: 0.0113

Alfa AF: 0.0126 Hom.: 7

Bravo AF: 0.0122

Asia WGS AF: 0.00202 AC: 7 AN: 3478

EpiCase AF: 0.0211

EpiControl AF: 0.0171

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Polycystic kidney disease, adult type Benign:2

Sep 25, 2018

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 09, 2017

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:2

Oct 28, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 10364515, 11857740, 17574468, 24374109) -

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Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Polycystic kidney disease Benign:1

-

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

The PKD1 p.Ala898Ala variant was identified in 24 of 1346 proband chromosomes (frequency: 0.02) from individuals or families with ADPKD (Garcia-Gonzalez 2007, McCluskey 2002, Peltola 2005, Rossetti 2002, Rossetti 2012, Tan 2009, Thomas 1999). The variant was identified in dbSNP (ID: rs142357713) as “N/A” and the ADPKD Mutation Database (as likely neutral). This variant was also identified in the 1000 Genomes Project in 33 of 5000 chromosomes (frequency: 0.007), the NHLBI GO Exome Sequencing Project in 188 of 8578 European American and in 16 of 4376 African American alleles, the Exome Aggregation Consortium database (August 8, 2016) in 1479 (11 homozygous) of 115044 chromosomes (freq. 0.01) in the following populations: European in 1216 of 62988 chromosomes (freq. 0.02), Finnish in 109 of 5876 chromosomes (freq. 0.02), Latino in 61 of 11260 chromosomes (freq. 0.005), South Asian in 45 of 16324 chromosomes (freq. 0.003), African in 39 of 9280 chromosomes (freq. 0.004), Other in 9 of 830 chromosomes (freq. 0.01), increasing the likelihood this could be a low frequency benign variant. However we cannot be certain that data from control databases is specific to PKD1 and not from one of the six PKD1 pseudogenes. The p.Ala898Ala 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. The variant occurs outside of the splicing consensus sequence and 1 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In addition, the variant is classified as a polymorphism by number of population and statistics studies (McCluskey 2002, Peltola 2005, Rossetti 2002, Rossetti 2012, Tan 2009, Thomas 1999). 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	-0.92
CADD	Benign	0.27
DANN	Benign	0.47

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: rs142357713; hg19: chr16-2164330;