rs79884128

Variant names:

• chr16-2110493-C-T
• rs79884128
• NM_001009944.3:c.4674G>A

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.4674G>A​(p.Thr1558Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0761 in 1,612,318 control chromosomes in the GnomAD database, including 5,388 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.064 (411 hom., cov: 34)
  • Exomes 𝑓: 0.077 (4977 hom.)
• Consequence: PKD1 NM_001009944.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -5.18
• 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: Orphanet, ClinGen
• 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=-0.71).
• BP6: Variant 16-2110493-C-T is Benign according to our data. Variant chr16-2110493-C-T is described in ClinVar as Benign. ClinVar VariationId is 256969.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-5.18 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.177 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PKD1	NM_001009944.3	MANE Select	c.4674G>A	p.Thr1558Thr	synonymous	Exon 15 of 46	NP_001009944.3	P98161-1
	PKD1	NM_000296.4		c.4674G>A	p.Thr1558Thr	synonymous	Exon 15 of 46	NP_000287.4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PKD1	ENST00000262304.9	TSL:1 MANE Select	c.4674G>A	p.Thr1558Thr	synonymous	Exon 15 of 46	ENSP00000262304.4	P98161-1
	PKD1	ENST00000423118.5	TSL:1	c.4674G>A	p.Thr1558Thr	synonymous	Exon 15 of 46	ENSP00000399501.1	P98161-3
	PKD1	ENST00000488185.2	TSL:5	c.471-2135G>A		intron	N/A	ENSP00000456672.1	H3BSE9

Frequencies

GnomAD3 genomes AF: 0.0637 AC: 9694 AN: 152194 Hom.: 410 Cov.: 34

Gnomad AFR AF: 0.0131

Gnomad AMI AF: 0.134

Gnomad AMR AF: 0.0509

Gnomad ASJ AF: 0.103

Gnomad EAS AF: 0.186

Gnomad SAS AF: 0.0708

Gnomad FIN AF: 0.0851

Gnomad MID AF: 0.101

Gnomad NFE AF: 0.0808

Gnomad OTH AF: 0.0722

GnomAD2 exomes AF: 0.0769 AC: 19137 AN: 248748 AF XY: 0.0783

Gnomad AFR exome AF: 0.00968

Gnomad AMR exome AF: 0.0492

Gnomad ASJ exome AF: 0.0968

Gnomad EAS exome AF: 0.180

Gnomad FIN exome AF: 0.0878

Gnomad NFE exome AF: 0.0754

Gnomad OTH exome AF: 0.0725

GnomAD4 exome AF: 0.0775 AC: 113080 AN: 1460006 Hom.: 4977 Cov.: 37 AF XY: 0.0781 AC XY: 56758 AN XY: 726292

African (AFR) AF: 0.0114 AC: 383 AN: 33466

American (AMR) AF: 0.0490 AC: 2190 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.0960 AC: 2507 AN: 26128

East Asian (EAS) AF: 0.212 AC: 8423 AN: 39700

South Asian (SAS) AF: 0.0747 AC: 6444 AN: 86238

European-Finnish (FIN) AF: 0.0923 AC: 4796 AN: 51934

Middle Eastern (MID) AF: 0.0898 AC: 509 AN: 5668

European-Non Finnish (NFE) AF: 0.0750 AC: 83358 AN: 1111814

Other (OTH) AF: 0.0741 AC: 4470 AN: 60348

GnomAD4 genome AF: 0.0636 AC: 9686 AN: 152312 Hom.: 411 Cov.: 34 AF XY: 0.0646 AC XY: 4808 AN XY: 74468

African (AFR) AF: 0.0131 AC: 545 AN: 41580

American (AMR) AF: 0.0508 AC: 777 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.103 AC: 356 AN: 3470

East Asian (EAS) AF: 0.186 AC: 967 AN: 5188

South Asian (SAS) AF: 0.0705 AC: 340 AN: 4824

European-Finnish (FIN) AF: 0.0851 AC: 903 AN: 10616

Middle Eastern (MID) AF: 0.0952 AC: 28 AN: 294

European-Non Finnish (NFE) AF: 0.0808 AC: 5498 AN: 68010

Other (OTH) AF: 0.0710 AC: 150 AN: 2114

Alfa AF: 0.0713 Hom.: 190

Bravo AF: 0.0588

Asia WGS AF: 0.0920 AC: 319 AN: 3478

EpiCase AF: 0.0769

EpiControl AF: 0.0736

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.71
CADD	Benign	0.10
DANN	Benign	0.88
PhyloP100		-5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=92/8	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs79884128; hg19: chr16-2160494; COSMIC: COSV51916911; COSMIC: COSV51916911;