16-2093916-GACAGCCACAGCC-GACAGCCACAGCCACAGCC

Variant names:

• chr16-2093916-G-GACAGCC
• rs777460677
• NM_001009944.3:c.10710_10715dupGGCTGT

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM1 PM4 PP5

The NM_001009944.3(PKD1):​c.10710_10715dupGGCTGT​(p.Val3572_Ser3573insAlaVal) variant causes a disruptive inframe insertion change. The variant allele was found at a frequency of 0.00000629 in 1,430,328 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000063 (0 hom.)
• Consequence: PKD1 NM_001009944.3 disruptive_inframe_insertion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:2
• Conservation: PhyloP100: 5.46
• 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-AS1 (HGNC:56035): (PKD1 antisense RNA 1)

ACMG classification

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_001009944.3
• PM4: Nonframeshift variant in NON repetitive region in NM_001009944.3.
• PP5: Variant 16-2093916-G-GACAGCC is Pathogenic according to our data. Variant chr16-2093916-G-GACAGCC is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 438650.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001009944.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PKD1	NM_001009944.3	MANE Select	c.10710_10715dupGGCTGT	p.Val3572_Ser3573insAlaVal	disruptive_inframe_insertion	Exon 36 of 46	NP_001009944.3
	PKD1	NM_000296.4		c.10707_10712dupGGCTGT	p.Val3571_Ser3572insAlaVal	disruptive_inframe_insertion	Exon 36 of 46	NP_000287.4
	PKD1-AS1	NR_135175.1		n.304-790_304-785dupAGCCAC		intron	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PKD1	ENST00000262304.9	TSL:1 MANE Select	c.10710_10715dupGGCTGT	p.Val3572_Ser3573insAlaVal	disruptive_inframe_insertion	Exon 36 of 46	ENSP00000262304.4
	PKD1	ENST00000423118.5	TSL:1	c.10707_10712dupGGCTGT	p.Val3571_Ser3572insAlaVal	disruptive_inframe_insertion	Exon 36 of 46	ENSP00000399501.1
	PKD1	ENST00000472659.1	TSL:3	n.147_152dupGGCTGT		non_coding_transcript_exon	Exon 2 of 4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000493 AC: 1 AN: 202676 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000111

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000629 AC: 9 AN: 1430328 Hom.: 0 Cov.: 33 AF XY: 0.00000141 AC XY: 1 AN XY: 709992

African (AFR) AF: 0.00 AC: 0 AN: 32924

American (AMR) AF: 0.00 AC: 0 AN: 42066

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25738

East Asian (EAS) AF: 0.00 AC: 0 AN: 38448

South Asian (SAS) AF: 0.00 AC: 0 AN: 83242

European-Finnish (FIN) AF: 0.0000240 AC: 1 AN: 41648

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5746

European-Non Finnish (NFE) AF: 0.00000727 AC: 8 AN: 1101126

Other (OTH) AF: 0.00 AC: 0 AN: 59390

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Polycystic kidney disease, adult type Pathogenic:1 Uncertain:1

May 22, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Apr 20, 2017

Bioscientia Institut fuer Medizinische Diagnostik GmbH, Sonic Healthcare

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

not provided Uncertain:1

Mar 31, 2025

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Identified with an additional variant on the opposite allele (in trans) in a patient with early-onset cystic nephropathy in published literature (PMID: 37372410); In-frame duplication of 2 amino acid(s) with an unclear effect on protein function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 37372410)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		5.5
Mutation Taster		=65/35	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs777460677; hg19: chr16-2143917;