rs35667726

Variant names:

• chr16-2114323-C-T
• rs35667726
• NM_001009944.3:c.2700G>A

Your query was ambiguous. Multiple possible variants found:

• chr16-2114323-C-T
• chr16-2114323-C-A
• chr16-2114323-C-G

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.2700G>A​(p.Pro900Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0621 in 1,610,282 control chromosomes in the GnomAD database, including 3,501 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.050 (271 hom., cov: 33)
  • Exomes 𝑓: 0.063 (3230 hom.)
• Consequence: PKD1 NM_001009944.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -4.44
• Publications: 16 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=-0.84).
• BP6: Variant 16-2114323-C-T is Benign according to our data. Variant chr16-2114323-C-T is described in ClinVar as Benign. ClinVar VariationId is 256936.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-4.44 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0644 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.2700G>A	p.Pro900Pro	synonymous	Exon 11 of 46	NP_001009944.3	P98161-1
	PKD1	NM_000296.4		c.2700G>A	p.Pro900Pro	synonymous	Exon 11 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.2700G>A	p.Pro900Pro	synonymous	Exon 11 of 46	ENSP00000262304.4	P98161-1
	PKD1	ENST00000423118.5	TSL:1	c.2700G>A	p.Pro900Pro	synonymous	Exon 11 of 46	ENSP00000399501.1	P98161-3
	PKD1	ENST00000488185.2	TSL:5	c.470+3166G>A		intron	N/A	ENSP00000456672.1	H3BSE9

Frequencies

GnomAD3 genomes AF: 0.0499 AC: 7589 AN: 152220 Hom.: 271 Cov.: 33

Gnomad AFR AF: 0.0128

Gnomad AMI AF: 0.0110

Gnomad AMR AF: 0.0478

Gnomad ASJ AF: 0.0772

Gnomad EAS AF: 0.000964

Gnomad SAS AF: 0.0437

Gnomad FIN AF: 0.115

Gnomad MID AF: 0.0475

Gnomad NFE AF: 0.0660

Gnomad OTH AF: 0.0492

GnomAD2 exomes AF: 0.0546 AC: 13552 AN: 248098 AF XY: 0.0564

Gnomad AFR exome AF: 0.0103

Gnomad AMR exome AF: 0.0289

Gnomad ASJ exome AF: 0.0860

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.112

Gnomad NFE exome AF: 0.0672

Gnomad OTH exome AF: 0.0606

GnomAD4 exome AF: 0.0634 AC: 92367 AN: 1457944 Hom.: 3230 Cov.: 34 AF XY: 0.0631 AC XY: 45735 AN XY: 725310

African (AFR) AF: 0.0103 AC: 345 AN: 33392

American (AMR) AF: 0.0295 AC: 1320 AN: 44694

Ashkenazi Jewish (ASJ) AF: 0.0881 AC: 2299 AN: 26110

East Asian (EAS) AF: 0.000151 AC: 6 AN: 39692

South Asian (SAS) AF: 0.0416 AC: 3587 AN: 86142

European-Finnish (FIN) AF: 0.113 AC: 5888 AN: 52146

Middle Eastern (MID) AF: 0.0542 AC: 224 AN: 4136

European-Non Finnish (NFE) AF: 0.0676 AC: 75184 AN: 1111472

Other (OTH) AF: 0.0584 AC: 3514 AN: 60160

GnomAD4 genome AF: 0.0498 AC: 7585 AN: 152338 Hom.: 271 Cov.: 33 AF XY: 0.0527 AC XY: 3923 AN XY: 74490

African (AFR) AF: 0.0128 AC: 531 AN: 41588

American (AMR) AF: 0.0478 AC: 731 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.0772 AC: 268 AN: 3470

East Asian (EAS) AF: 0.000966 AC: 5 AN: 5176

South Asian (SAS) AF: 0.0435 AC: 210 AN: 4828

European-Finnish (FIN) AF: 0.115 AC: 1225 AN: 10624

Middle Eastern (MID) AF: 0.0408 AC: 12 AN: 294

European-Non Finnish (NFE) AF: 0.0660 AC: 4490 AN: 68026

Other (OTH) AF: 0.0487 AC: 103 AN: 2116

Alfa AF: 0.0527 Hom.: 80

Bravo AF: 0.0417

Asia WGS AF: 0.0230 AC: 81 AN: 3478

EpiCase AF: 0.0674

EpiControl AF: 0.0618

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.11
DANN	Benign	0.65
PhyloP100		-4.4
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.6
Mutation Taster		=100/0	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: rs35667726; hg19: chr16-2164324; COSMIC: COSV51916452; COSMIC: COSV51916452;