rs376744819

chr16-2109068-C-T

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_001009944.3(PKD1):c.6099G>A(p.Ala2033=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00028 in 1,605,992 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00017 (1 hom., cov: 33)
  • Exomes 𝑓: 0.00029 (1 hom.)
• Consequence: PKD1 NM_001009944.3 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -4.69

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 -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 16-2109068-C-T is Benign according to our data. Variant chr16-2109068-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 433969.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2109068-C-T is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-4.69 with no splicing effect.
• BS2: High AC in GnomAd at 26 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PKD1	NM_001009944.3	c.6099G>A	p.Ala2033=	synonymous_variant	15/46	ENST00000262304.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PKD1	ENST00000262304.9	c.6099G>A	p.Ala2033=	synonymous_variant	15/46	1	NM_001009944.3	P5

Frequencies

GnomAD3 genomes AF: 0.000171 AC: 26 AN: 152246 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000963

Gnomad SAS AF: 0.00248

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000564 AC: 138 AN: 244514 Hom.: 1 AF XY: 0.000725 AC XY: 97 AN XY: 133782

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00150

Gnomad SAS exome AF: 0.00197

Gnomad FIN exome AF: 0.0000474

Gnomad NFE exome AF: 0.000457

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000291 AC: 423 AN: 1453628 Hom.: 1 Cov.: 34 AF XY: 0.000355 AC XY: 256 AN XY: 721878

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.0000384

Gnomad4 EAS exome AF: 0.000735

Gnomad4 SAS exome AF: 0.00238

Gnomad4 FIN exome AF: 0.000175

Gnomad4 NFE exome AF: 0.000147

Gnomad4 OTH exome AF: 0.000267

GnomAD4 genome AF: 0.000171 AC: 26 AN: 152364 Hom.: 1 Cov.: 33 AF XY: 0.000255 AC XY: 19 AN XY: 74512

Gnomad4 AFR AF: 0.0000240

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000965

Gnomad4 SAS AF: 0.00249

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000118

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000223 Hom.: 0

Bravo AF: 0.000170

EpiCase AF: 0.000218

EpiControl AF: 0.000296

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Polycystic kidney disease Benign:1

Likely benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The PKD1, p.Ala2033Ala variant was not identified in the literature, nor was it identified in the Clinvitae, ClinVar, MutDB, PKD1-LOVD and PKD1-LOVD 3.0 databases. This variant has been seen in one individual from our laboratory as co-occurring with a pathogenic variant increasing the likelihood it may not have clinical significance. The variant was identified in dbSNP (ID: rs376744819) as “N/A”. This variant was also identified in the 1000 Genomes Project in 5 of 5000 chromosomes (frequency: 0.001); NHLBI GO Exome Sequencing Project in 2 of 8570 European American and not found in African American alleles; in the Exome Aggregation Consortium database (March 14, 2016) in 93 (1 homozygous) of 114196 chromosomes (freq. 0.0008) in the following populations: East Asian in 16 of 8378 chromosomes (freq. 0.002), South Asian in 30 of 16244 chromosomes (freq. 0.002), European (Non-Finnish) in 46 of 62058 chromosomes (freq. 0.0007), and Finnish in 1 of 6366 chromosomes (freq. 0.0002), but was not seen in African, Latino and Other populations, increasing the likelihood this could be a low frequency benign variant. We are not able to rule out that variant data from control databases is specific to PKD1 and not from one of the six PKD1 pseudogenes. The variant was also identified in ADPKD Mutation Database classified as Likely Neutral. The p.Ala2033Ala 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 4 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% chance that the variant creats a 3’ splice site. However, this information is not predictive enough to assume pathogenicity. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign. -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Jul 20, 2020

- -

PKD1-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 04, 2021

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
Cadd	Benign	0.16
Dann	Benign	0.90
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs376744819; hg19: chr16-2159069; COSMIC: COSV51916162; COSMIC: COSV51916162;