16-2109068-C-T

Variant names:

• chr16-2109068-C-T
• rs376744819
• NM_001009944.3:c.6099G>A

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS1

The NM_001009944.3(PKD1):​c.6099G>A​(p.Ala2033Ala) 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:4
• Conservation: PhyloP100: -4.69
• Publications: 1 publications found

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 Gene-Disease associations (from GenCC):

• autosomal dominant polycystic kidney disease

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• polycystic kidney disease 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Laboratory for Molecular Medicine, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• autosomal recessive polycystic kidney disease

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• Caroli disease

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp

ACMG classification

Our verdict: Benign. The variant received -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.
• BP7: Synonymous conserved (PhyloP=-4.69 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000171 (26/152364) while in subpopulation SAS AF = 0.00249 (12/4828). AF 95% confidence interval is 0.00143. There are 1 homozygotes in GnomAd4. There are 19 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PKD1	NM_001009944.3	c.6099G>A	p.Ala2033Ala	synonymous_variant	Exon 15 of 46	ENST00000262304.9	NP_001009944.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PKD1	ENST00000262304.9	c.6099G>A	p.Ala2033Ala	synonymous_variant	Exon 15 of 46	1	NM_001009944.3	ENSP00000262304.4

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

GnomAD2 exomes AF: 0.000564 AC: 138 AN: 244514 AF XY: 0.000725

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 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

African (AFR) AF: 0.00 AC: 0 AN: 33350

American (AMR) AF: 0.00 AC: 0 AN: 44568

Ashkenazi Jewish (ASJ) AF: 0.0000384 AC: 1 AN: 26054

East Asian (EAS) AF: 0.000735 AC: 29 AN: 39482

South Asian (SAS) AF: 0.00238 AC: 205 AN: 86090

European-Finnish (FIN) AF: 0.000175 AC: 9 AN: 51510

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5300

European-Non Finnish (NFE) AF: 0.000147 AC: 163 AN: 1107336

Other (OTH) AF: 0.000267 AC: 16 AN: 59938

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

African (AFR) AF: 0.0000240 AC: 1 AN: 41596

American (AMR) AF: 0.00 AC: 0 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.000965 AC: 5 AN: 5180

South Asian (SAS) AF: 0.00249 AC: 12 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10632

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000118 AC: 8 AN: 68028

Other (OTH) AF: 0.00 AC: 0 AN: 2116

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:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jul 20, 2020

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Polycystic kidney disease Benign:1

-

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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. -

PKD1-related disorder Benign:1

Oct 04, 2021

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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
PhyloP100		-4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=90/10	polymorphism

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

Other links and lift over

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