rs776302294

Positions:

• chr16-2118404-G-A

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_001009944.3(PKD1):​c.588C>T​(p.Ser196=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00123 in 1,221,104 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 Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0012 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0012 (11 hom.)
• Consequence: PKD1 NM_001009944.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 1.88

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 -16 ACMG points.

• BP6: Variant 16-2118404-G-A is Benign according to our data. Variant chr16-2118404-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 256985.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2118404-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.00124 (1321/1068932) while in subpopulation MID AF= 0.0118 (41/3474). AF 95% confidence interval is 0.00894. There are 11 homozygotes in gnomad4_exome. There are 664 alleles in male gnomad4_exome subpopulation. Median coverage is 14. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 176 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PKD1	NM_001009944.3	c.588C>T	p.Ser196=	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.588C>T	p.Ser196=	synonymous_variant	5/46	1	NM_001009944.3	ENSP00000262304	P5
PKD1	ENST00000423118.5	c.588C>T	p.Ser196=	synonymous_variant	5/46	1		ENSP00000399501	A2

Frequencies

GnomAD3 genomes AF: 0.00116 AC: 176 AN: 152054 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000217

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00105

Gnomad ASJ AF: 0.0242

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000839

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.00250 AC: 335 AN: 134196 Hom.: 4 AF XY: 0.00226 AC XY: 165 AN XY: 73054

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000778

Gnomad ASJ exome AF: 0.0264

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000842

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00129

Gnomad OTH exome AF: 0.00341

GnomAD4 exome AF: 0.00124 AC: 1321 AN: 1068932 Hom.: 11 Cov.: 14 AF XY: 0.00123 AC XY: 664 AN XY: 540998

Gnomad4 AFR exome AF: 0.000314

Gnomad4 AMR exome AF: 0.000703

Gnomad4 ASJ exome AF: 0.0258

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000857

Gnomad4 FIN exome AF: 0.0000298

Gnomad4 NFE exome AF: 0.000565

Gnomad4 OTH exome AF: 0.00288

GnomAD4 genome AF: 0.00116 AC: 176 AN: 152172 Hom.: 1 Cov.: 32 AF XY: 0.00105 AC XY: 78 AN XY: 74404

Gnomad4 AFR AF: 0.000217

Gnomad4 AMR AF: 0.00105

Gnomad4 ASJ AF: 0.0242

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.0000942

Gnomad4 NFE AF: 0.000839

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.00371 Hom.: 1

Bravo AF: 0.00141

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 20, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Mar 13, 2017	- -

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 14, 2020	This variant is associated with the following publications: (PMID: 17574468) -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2023	PKD1: BS1, BS2 -

Polycystic kidney disease, adult type Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Aug 10, 2021

- -

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.Ser196= variant was identified in 2 of 164 proband chromosomes (frequency: 0.01) from individuals or families with ADPKD (Garcia-Gonzalez 2007). The variant was also identified in dbSNP (ID: rs776302294) as "With other allele ", ClinVar (classified as benign by Athena Diagnostics; as likely benign by PreventionGenetics and ARUP), and in ADPKD Mutation Database (likely neutral). The variant was not identified in LOVD 3.0, or PKD1-LOVD, databases. The variant was identified in control databases in 342 of 159848 chromosomes (3 homozygous) at a frequency of 0.002 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 1 of 14724 chromosomes (freq: 0.00007), Other in 14 of 4544 chromosomes (freq: 0.003), Latino in 18 of 24560 chromosomes (freq: 0.0007), European in 78 of 64948 chromosomes (freq: 0.001), Ashkenazi Jewish in 212 of 8190 chromosomes (freq: 0.03), and South Asian in 19 of 22622 chromosomes (freq: 0.0008), while the variant was not observed in the East Asian, and 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.Ser196= 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. In addition, in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. 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	-0.82
CADD	Benign	15
DANN	Benign	0.69

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.40		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.40		Position offset: -8

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs776302294; hg19: chr16-2168405;