16-2117873-G-A

Variant names:

• chr16-2117873-G-A
• rs35842
• NM_001009944.3:c.1119C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001009944.3(PKD1):​c.1119C>T​(p.Leu373Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.83 in 142,122 control chromosomes in the GnomAD database, including 48,164 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.83 (48164 hom., cov: 30)
  • Exomes 𝑓: 0.78 (295723 hom.)
  • Failed GnomAD Quality Control
• Consequence: PKD1 NM_001009944.3 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.08
• Publications: 12 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 Gene-Disease associations (from GenCC):

• autosomal dominant polycystic kidney disease

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• polycystic kidney disease 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Laboratory for Molecular Medicine, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• autosomal recessive polycystic kidney disease

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• Caroli disease

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 16-2117873-G-A is Benign according to our data. Variant chr16-2117873-G-A is described in ClinVar as Benign. ClinVar VariationId is 803174.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.08 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.94 is higher than 0.05.

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.1119C>T	p.Leu373Leu	synonymous	Exon 5 of 46	NP_001009944.3
	PKD1	NM_000296.4		c.1119C>T	p.Leu373Leu	synonymous	Exon 5 of 46	NP_000287.4

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PKD1	ENST00000262304.9	TSL:1 MANE Select	c.1119C>T	p.Leu373Leu	synonymous	Exon 5 of 46	ENSP00000262304.4
	PKD1	ENST00000423118.5	TSL:1	c.1119C>T	p.Leu373Leu	synonymous	Exon 5 of 46	ENSP00000399501.1
	PKD1	ENST00000488185.2	TSL:5	c.204C>T	p.Leu68Leu	synonymous	Exon 1 of 5	ENSP00000456672.1

Frequencies

GnomAD3 genomes AF: 0.829 AC: 117786 AN: 142016 Hom.: 48111 Cov.: 30

Gnomad AFR AF: 0.906

Gnomad AMI AF: 0.710

Gnomad AMR AF: 0.856

Gnomad ASJ AF: 0.767

Gnomad EAS AF: 0.963

Gnomad SAS AF: 0.889

Gnomad FIN AF: 0.814

Gnomad MID AF: 0.825

Gnomad NFE AF: 0.771

Gnomad OTH AF: 0.815

GnomAD2 exomes AF: 0.895 AC: 84660 AN: 94572 AF XY: 0.894

Gnomad AFR exome AF: 0.974

Gnomad AMR exome AF: 0.930

Gnomad ASJ exome AF: 0.820

Gnomad EAS exome AF: 1.00

Gnomad FIN exome AF: 0.847

Gnomad NFE exome AF: 0.829

Gnomad OTH exome AF: 0.860

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.778 AC: 788669 AN: 1014150 Hom.: 295723 Cov.: 15 AF XY: 0.779 AC XY: 399855 AN XY: 513052

African (AFR) AF: 0.890 AC: 21374 AN: 24004

American (AMR) AF: 0.879 AC: 30591 AN: 34792

Ashkenazi Jewish (ASJ) AF: 0.756 AC: 16971 AN: 22440

East Asian (EAS) AF: 0.914 AC: 30799 AN: 33690

South Asian (SAS) AF: 0.842 AC: 60604 AN: 71958

European-Finnish (FIN) AF: 0.799 AC: 27115 AN: 33930

Middle Eastern (MID) AF: 0.782 AC: 2613 AN: 3342

European-Non Finnish (NFE) AF: 0.756 AC: 562781 AN: 744750

Other (OTH) AF: 0.792 AC: 35821 AN: 45244

GnomAD4 genome AF: 0.830 AC: 117892 AN: 142122 Hom.: 48164 Cov.: 30 AF XY: 0.833 AC XY: 57768 AN XY: 69370

African (AFR) AF: 0.906 AC: 34638 AN: 38240

American (AMR) AF: 0.856 AC: 12327 AN: 14396

Ashkenazi Jewish (ASJ) AF: 0.767 AC: 2507 AN: 3270

East Asian (EAS) AF: 0.963 AC: 4667 AN: 4848

South Asian (SAS) AF: 0.888 AC: 3917 AN: 4410

European-Finnish (FIN) AF: 0.814 AC: 8214 AN: 10092

Middle Eastern (MID) AF: 0.818 AC: 229 AN: 280

European-Non Finnish (NFE) AF: 0.771 AC: 49211 AN: 63808

Other (OTH) AF: 0.817 AC: 1598 AN: 1956

Alfa AF: 0.802 Hom.: 4452

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.85
DANN	Benign	0.83
PhyloP100		-1.1
PromoterAI		0.033	Neutral
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs35842; hg19: chr16-2167874; COSMIC: COSV51919086; COSMIC: COSV51919086;