rs149938033

chr16-2110904-G-Achr16-2110904-G-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.4263C>T(p.Ala1421=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000828 in 1,611,438 control chromosomes in the GnomAD database, including 12 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0034 (5 hom., cov: 33)
  • Exomes 𝑓: 0.00056 (7 hom.)
• Consequence: PKD1 NM_001009944.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.952

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=-0.82).
• BP6: Variant 16-2110904-G-A is Benign according to our data. Variant chr16-2110904-G-A is described in ClinVar as [Benign]. Clinvar id is 256963.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2110904-G-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-0.952 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00337 (514/152340) while in subpopulation AFR AF= 0.0111 (460/41576). AF 95% confidence interval is 0.0102. There are 5 homozygotes in gnomad4. There are 246 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 513 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PKD1	NM_001009944.3	c.4263C>T	p.Ala1421=	synonymous_variant	15/46	ENST00000262304.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PKD1	ENST00000262304.9	c.4263C>T	p.Ala1421=	synonymous_variant	15/46	1	NM_001009944.3	P5

Frequencies

GnomAD3 genomes AF: 0.00337 AC: 513 AN: 152222 Hom.: 5 Cov.: 33

Gnomad AFR AF: 0.0111

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00137

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000220

Gnomad OTH AF: 0.00478

GnomAD3 exomes AF: 0.00104 AC: 258 AN: 248922 Hom.: 2 AF XY: 0.000768 AC XY: 104 AN XY: 135342

Gnomad AFR exome AF: 0.0129

Gnomad AMR exome AF: 0.000376

Gnomad ASJ exome AF: 0.00140

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.000197

Gnomad OTH exome AF: 0.000329

GnomAD4 exome AF: 0.000563 AC: 821 AN: 1459098 Hom.: 7 Cov.: 36 AF XY: 0.000532 AC XY: 386 AN XY: 725836

Gnomad4 AFR exome AF: 0.0127

Gnomad4 AMR exome AF: 0.000358

Gnomad4 ASJ exome AF: 0.00165

Gnomad4 EAS exome AF: 0.000126

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.0000576

Gnomad4 NFE exome AF: 0.000238

Gnomad4 OTH exome AF: 0.00105

GnomAD4 genome AF: 0.00337 AC: 514 AN: 152340 Hom.: 5 Cov.: 33 AF XY: 0.00330 AC XY: 246 AN XY: 74486

Gnomad4 AFR AF: 0.0111

Gnomad4 AMR AF: 0.00137

Gnomad4 ASJ AF: 0.00173

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000941

Gnomad4 NFE AF: 0.000221

Gnomad4 OTH AF: 0.00473

Alfa AF: 0.000644 Hom.: 0

Bravo AF: 0.00400

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000218

EpiControl AF: 0.000119

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	May 11, 2021	This variant is associated with the following publications: (PMID: 22383692) -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	May 10, 2019	- -

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

Oct 01, 2018

- -

Polycystic kidney disease Benign:1

Benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The PKD1 p.Ala1421= variant was identified in 3 of 550 proband chromosomes (frequency: 0.005) from individuals or families with ADPKD (Rossetti 2002, Rossetti 2012). The variant was also identified in dbSNP (ID: rs149938033) as “With Benign allele”, Clinvitae (classification benign), ClinVar (classification benign by Prevention Genetics), ADPKD Mutation Database (classification likely neutral), the 1000 Genomes Project in 16 of 5000 chromosomes (frequency: 0.003), HAPMAP-AFR in 16 of 1322 chromosomes (frequency: 0.01), NHLBI GO Exome Sequencing Project in 4 of 8592 European American American alleles (frequency: 0.0005) and in 52 of 4394 African American alleles (frequency: 0.01), and in the Exome Aggregation Consortium database (August 8, 2016) in 141 (2 homozygous) of 118562 chromosomes (frequency: 0.001), increasing the likelihood this could be a low frequency benign variant. In addition we cannot be certain that data from control databases is specific to PKD1 and not from one of the six PKD1 pseudogenes. The variant was not identified in GeneInsight COGR, MutDB, PKD1-LOVD, and PKD1-LOVD 3.0. The c.4263C>T 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, occurring outside of the splicing consensus sequence. In addition one of five in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predicting a greater than 10% difference in splicing; this is not very predictive of pathogenicity. The variant was identified with a co-occurring pathogenic PKD2 variant (c.709+1G>A, r.spl?), increasing the likelihood that the c.4263C>T variant does not have clinical significance. 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	-0.82
Cadd	Benign	0.56
Dann	Benign	0.55

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: rs149938033; hg19: chr16-2160905;