rs35965348

Variant names:

• chr16-2114293-G-A
• rs35965348
• NM_001009944.3:c.2730C>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.2730C>T​(p.Asp910Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.062 in 1,610,168 control chromosomes in the GnomAD database, including 3,487 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.050 (269 hom., cov: 32)
  • Exomes 𝑓: 0.063 (3218 hom.)
• Consequence: PKD1 NM_001009944.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -1.50
• Publications: 14 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=-0.72).
• BP6: Variant 16-2114293-G-A is Benign according to our data. Variant chr16-2114293-G-A is described in ClinVar as Benign. ClinVar VariationId is 256937.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.5 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0645 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.2730C>T	p.Asp910Asp	synonymous	Exon 11 of 46	NP_001009944.3	P98161-1
	PKD1	NM_000296.4		c.2730C>T	p.Asp910Asp	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.2730C>T	p.Asp910Asp	synonymous	Exon 11 of 46	ENSP00000262304.4	P98161-1
	PKD1	ENST00000423118.5	TSL:1	c.2730C>T	p.Asp910Asp	synonymous	Exon 11 of 46	ENSP00000399501.1	P98161-3
	PKD1	ENST00000488185.2	TSL:5	c.470+3196C>T		intron	N/A	ENSP00000456672.1	H3BSE9

Frequencies

GnomAD3 genomes AF: 0.0497 AC: 7560 AN: 152184 Hom.: 269 Cov.: 32

Gnomad AFR AF: 0.0129

Gnomad AMI AF: 0.0110

Gnomad AMR AF: 0.0456

Gnomad ASJ AF: 0.0772

Gnomad EAS AF: 0.000965

Gnomad SAS AF: 0.0434

Gnomad FIN AF: 0.115

Gnomad MID AF: 0.0475

Gnomad NFE AF: 0.0661

Gnomad OTH AF: 0.0492

GnomAD2 exomes AF: 0.0545 AC: 13532 AN: 248208 AF XY: 0.0563

Gnomad AFR exome AF: 0.0105

Gnomad AMR exome AF: 0.0285

Gnomad ASJ exome AF: 0.0858

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.112

Gnomad NFE exome AF: 0.0671

Gnomad OTH exome AF: 0.0608

GnomAD4 exome AF: 0.0633 AC: 92251 AN: 1457866 Hom.: 3218 Cov.: 34 AF XY: 0.0630 AC XY: 45692 AN XY: 725284

African (AFR) AF: 0.0103 AC: 343 AN: 33398

American (AMR) AF: 0.0291 AC: 1302 AN: 44688

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

East Asian (EAS) AF: 0.000101 AC: 4 AN: 39690

South Asian (SAS) AF: 0.0417 AC: 3592 AN: 86152

European-Finnish (FIN) AF: 0.113 AC: 5888 AN: 52130

Middle Eastern (MID) AF: 0.0544 AC: 225 AN: 4136

European-Non Finnish (NFE) AF: 0.0676 AC: 75085 AN: 1111414

Other (OTH) AF: 0.0584 AC: 3513 AN: 60148

GnomAD4 genome AF: 0.0496 AC: 7558 AN: 152302 Hom.: 269 Cov.: 32 AF XY: 0.0523 AC XY: 3897 AN XY: 74478

African (AFR) AF: 0.0128 AC: 534 AN: 41580

American (AMR) AF: 0.0456 AC: 698 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0772 AC: 268 AN: 3472

East Asian (EAS) AF: 0.000967 AC: 5 AN: 5172

South Asian (SAS) AF: 0.0432 AC: 209 AN: 4834

European-Finnish (FIN) AF: 0.115 AC: 1224 AN: 10610

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

European-Non Finnish (NFE) AF: 0.0661 AC: 4495 AN: 68014

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

Alfa AF: 0.0601 Hom.: 126

Bravo AF: 0.0415

Asia WGS AF: 0.0230 AC: 81 AN: 3478

EpiCase AF: 0.0674

EpiControl AF: 0.0617

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	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	-0.72
CADD	Benign	0.86
DANN	Benign	0.75
PhyloP100		-1.5
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: rs35965348; hg19: chr16-2164294; COSMIC: COSV51916443; COSMIC: COSV51916443;