16-2118155-C-T

Position:

• chr16-2118155-C-T

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.837G>A​(p.Gly279=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00135 in 1,581,796 control chromosomes in the GnomAD database, including 28 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0021 (4 hom., cov: 32)
  • Exomes 𝑓: 0.0013 (24 hom.)
• Consequence: PKD1 NM_001009944.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.702

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=-0.48).
• BP6: Variant 16-2118155-C-T is Benign according to our data. Variant chr16-2118155-C-T is described in ClinVar as [Benign]. Clinvar id is 257019.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2118155-C-T is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-0.702 with no splicing effect.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00207 (316/152290) while in subpopulation AMR AF= 0.018 (276/15310). AF 95% confidence interval is 0.0163. There are 4 homozygotes in gnomad4. There are 158 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 316 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PKD1	NM_001009944.3	c.837G>A	p.Gly279=	synonymous_variant	5/46	ENST00000262304.9	NP_001009944.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PKD1	ENST00000262304.9	c.837G>A	p.Gly279=	synonymous_variant	5/46	1	NM_001009944.3	ENSP00000262304	P5
PKD1	ENST00000423118.5	c.837G>A	p.Gly279=	synonymous_variant	5/46	1		ENSP00000399501	A2
PKD1	ENST00000570150.1			upstream_gene_variant		5

Frequencies

GnomAD3 genomes AF: 0.00205 AC: 312 AN: 152172 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0178

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00213

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.00575 AC: 1045 AN: 181794 Hom.: 14 AF XY: 0.00433 AC XY: 433 AN XY: 100042

Gnomad AFR exome AF: 0.000315

Gnomad AMR exome AF: 0.0354

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00194

Gnomad SAS exome AF: 0.0000770

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000130

Gnomad OTH exome AF: 0.00533

GnomAD4 exome AF: 0.00128 AC: 1823 AN: 1429506 Hom.: 24 Cov.: 33 AF XY: 0.00113 AC XY: 803 AN XY: 709278

Gnomad4 AFR exome AF: 0.000275

Gnomad4 AMR exome AF: 0.0343

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00735

Gnomad4 SAS exome AF: 0.0000240

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000765

Gnomad4 OTH exome AF: 0.00113

GnomAD4 genome AF: 0.00207 AC: 316 AN: 152290 Hom.: 4 Cov.: 32 AF XY: 0.00212 AC XY: 158 AN XY: 74456

Gnomad4 AFR AF: 0.000481

Gnomad4 AMR AF: 0.0180

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00213

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000882

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.000384 Hom.: 0

Bravo AF: 0.00355

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Polycystic kidney disease, adult type Benign:2

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Feb 03, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Jul 07, 2021	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

Aug 27, 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.Gly279= variant was not identified in the literature nor was it identified in the LOVD 3.0 or PKD1-LOVD databases. The variant was identified in dbSNP (ID: rs372124319) as "With other allele", ClinVar (classified as benign by ARUP and Athena Diagnostics; as likely benign by Prevention Genetics), and in ADPKD Mutation Database (as Likely Neutral). The variant was identified in control databases in 1057 of 209002 chromosomes (16 homozygous) at a frequency of 0.005, increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 5 of 18078 chromosomes (freq: 0.0003), Other in 32 of 5288 chromosomes (freq: 0.006), Latino in 989 of 27992 chromosomes (freq: 0.04), European in 4 of 90316 chromosomes (freq: 0.00004), East Asian in 25 of 14370 chromosomes (freq: 0.002), and South Asian in 2 of 26106 chromosomes (freq: 0.00008), while the variant was not observed in the Ashkenazi Jewish or Finnish populations. 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 p.Gly279= 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. However, 1 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predicts a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In summary, based on the above information, this variant meets our laboratory criteria to be classified as benign. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jan 15, 2020

- -

PKD1-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 27, 2023

This variant is classified as 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	-0.48
CADD	Benign	9.4
DANN	Benign	0.65
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs372124319; hg19: chr16-2168156;