chr16-2093916-GACAGCC-G

Variant names:

• chr16-2093916-GACAGCC-G
• rs777460677
• NM_001009944.3:c.10710_10715delGGCTGT

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PM1 PM4 PP5_Very_Strong

The NM_001009944.3(PKD1):​c.10710_10715delGGCTGT​(p.Ala3571_Val3572del) variant causes a disruptive inframe deletion change. The variant allele was found at a frequency of 0.00000699 in 1,430,312 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000070 (0 hom.)
• Consequence: PKD1 NM_001009944.3 disruptive_inframe_deletion
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7
• 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: Pathogenic. The variant received 12 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, 5 uncertain in NM_001009944.3
• PM4: Nonframeshift variant in NON repetitive region in NM_001009944.3.
• PP5: Variant 16-2093916-GACAGCC-G is Pathogenic according to our data. Variant chr16-2093916-GACAGCC-G is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 434001.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PKD1	NM_001009944.3	MANE Select	c.10710_10715delGGCTGT	p.Ala3571_Val3572del	disruptive_inframe_deletion	Exon 36 of 46	NP_001009944.3	P98161-1
	PKD1	NM_000296.4		c.10707_10712delGGCTGT	p.Ala3570_Val3571del	disruptive_inframe_deletion	Exon 36 of 46	NP_000287.4
	PKD1-AS1	NR_135175.1		n.304-790_304-785delAGCCAC		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PKD1	ENST00000262304.9	TSL:1 MANE Select	c.10710_10715delGGCTGT	p.Ala3571_Val3572del	disruptive_inframe_deletion	Exon 36 of 46	ENSP00000262304.4	P98161-1
	PKD1	ENST00000423118.5	TSL:1	c.10707_10712delGGCTGT	p.Ala3570_Val3571del	disruptive_inframe_deletion	Exon 36 of 46	ENSP00000399501.1	P98161-3
	PKD1	ENST00000472659.1	TSL:3	n.147_152delGGCTGT		non_coding_transcript_exon	Exon 2 of 4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000699 AC: 10 AN: 1430312 Hom.: 0 AF XY: 0.00000845 AC XY: 6 AN XY: 709984

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

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

American (AMR) AF: 0.0000238 AC: 1 AN: 42060

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

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

South Asian (SAS) AF: 0.0000120 AC: 1 AN: 83242

European-Finnish (FIN) AF: 0.0000480 AC: 2 AN: 41644

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

European-Non Finnish (NFE) AF: 0.00000545 AC: 6 AN: 1101120

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

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000571497), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
4	-	-	Polycystic kidney disease, adult type (4)
2	-	-	not provided (2)
1	-	-	Autosomal dominant polycystic kidney disease (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		5.5
Mutation Taster		=36/164	disease causing (ClinVar)

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;