rs143013095

chr16-2112943-C-Gchr16-2112943-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.3006G>C(p.Val1002=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000946 in 1,601,998 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0011 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00093 (4 hom.)
• Consequence: PKD1 NM_001009944.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 1.80

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.52).
• BP6: Variant 16-2112943-C-G is Benign according to our data. Variant chr16-2112943-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 256940.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2112943-C-G is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=1.8 with no splicing effect.
• BS2: High AC in GnomAd at 163 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PKD1	NM_001009944.3	c.3006G>C	p.Val1002=	synonymous_variant	13/46	ENST00000262304.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PKD1	ENST00000262304.9	c.3006G>C	p.Val1002=	synonymous_variant	13/46	1	NM_001009944.3	P5
	ENST00000568795.1	n.161-104C>G		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.00107 AC: 163 AN: 152252 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000723

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00548

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00132

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00181

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.00120 AC: 292 AN: 242800 Hom.: 1 AF XY: 0.00122 AC XY: 162 AN XY: 132250

Gnomad AFR exome AF: 0.0000622

Gnomad AMR exome AF: 0.0000579

Gnomad ASJ exome AF: 0.00590

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00266

Gnomad NFE exome AF: 0.00160

Gnomad OTH exome AF: 0.00182

GnomAD4 exome AF: 0.000933 AC: 1353 AN: 1449628 Hom.: 4 Cov.: 34 AF XY: 0.000967 AC XY: 698 AN XY: 721468

Gnomad4 AFR exome AF: 0.000150

Gnomad4 AMR exome AF: 0.0000895

Gnomad4 ASJ exome AF: 0.00639

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00259

Gnomad4 NFE exome AF: 0.000905

Gnomad4 OTH exome AF: 0.000948

GnomAD4 genome AF: 0.00107 AC: 163 AN: 152370 Hom.: 0 Cov.: 32 AF XY: 0.000953 AC XY: 71 AN XY: 74504

Gnomad4 AFR AF: 0.0000721

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00548

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00132

Gnomad4 NFE AF: 0.00181

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.00248 Hom.: 0

Bravo AF: 0.000774

EpiCase AF: 0.00147

EpiControl AF: 0.000771

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2024	PKD1: BP4, BP7 -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 12, 2021	- -

Polycystic kidney disease, adult type Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 25, 2021

- -

PKD1-related condition Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 12, 2020

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). -

Polycystic kidney disease Benign:1

Likely benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The PKD1 c.3006G>C variant was not identified in the literature nor was it identified in the Clinvitae, ClinVar, GeneInsight COGR, MutDB, PKD1-LOVD, and PKD1-LOVD 3.0 databases. The variant was identified in dbSNP (ID: rs143013095) as “N/A”, and the ADPKD Mutation Database (classified as likely neutral by Athena Diagnostics). This variant was also identified in the 1000 Genomes Project in 2 of 5000 chromosomes (frequency: 0.0004), NHLBI GO Exome Sequencing Project in 8 of 8600 European American alleles, the Exome Aggregation Consortium database (August 8, 2016) in 136 of 119208 chromosomes (freq. 0.001) in the following populations: European in 122 of 65136 chromosomes (freq. 0.002), Finnish in 11 of 6556 chromosomes (freq. 0.002), Latino in 2 of 11502 chromosomes (freq. 0.0002) and Other in 1 of 880 chromosomes (freq. 0.001), although this low number of observations and low frequency is not substantive enough to determine the prevalence of the variant in the general population and its relationship to disease. The p.Val1002Val 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 3 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing. 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.52
Cadd	Benign	5.5
Dann	Benign	0.68
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs143013095; hg19: chr16-2162944;