rs117856830

Variant names:

• chr16-2103618-G-A
• rs117856830
• NM_001009944.3:c.8439C>T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_001009944.3(PKD1):​c.8439C>T​(p.Ser2813Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00801 in 1,610,454 control chromosomes in the GnomAD database, including 63 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0050 (4 hom., cov: 31)
  • Exomes 𝑓: 0.0083 (59 hom.)
• Consequence: PKD1 NM_001009944.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 0.112
• Publications: 3 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.42).
• BP6: Variant 16-2103618-G-A is Benign according to our data. Variant chr16-2103618-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 257020.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.112 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00499 (760/152310) while in subpopulation NFE AF = 0.00863 (587/68028). AF 95% confidence interval is 0.00805. There are 4 homozygotes in GnomAd4. There are 336 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 4 AD,AR gene

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.8439C>T	p.Ser2813Ser	synonymous	Exon 23 of 46	NP_001009944.3	P98161-1
	PKD1	NM_000296.4		c.8439C>T	p.Ser2813Ser	synonymous	Exon 23 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.8439C>T	p.Ser2813Ser	synonymous	Exon 23 of 46	ENSP00000262304.4	P98161-1
	PKD1	ENST00000423118.5	TSL:1	c.8439C>T	p.Ser2813Ser	synonymous	Exon 23 of 46	ENSP00000399501.1	P98161-3
	PKD1	ENST00000480227.5	TSL:1	n.176C>T		non_coding_transcript_exon	Exon 1 of 8

Frequencies

GnomAD3 genomes AF: 0.00499 AC: 760 AN: 152192 Hom.: 4 Cov.: 31

Gnomad AFR AF: 0.00125

Gnomad AMI AF: 0.0165

Gnomad AMR AF: 0.00301

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00269

Gnomad FIN AF: 0.00348

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00863

Gnomad OTH AF: 0.00287

GnomAD2 exomes AF: 0.00481 AC: 1198 AN: 248816 AF XY: 0.00485

Gnomad AFR exome AF: 0.00138

Gnomad AMR exome AF: 0.00217

Gnomad ASJ exome AF: 0.00231

Gnomad EAS exome AF: 0.0000545

Gnomad FIN exome AF: 0.00269

Gnomad NFE exome AF: 0.00854

Gnomad OTH exome AF: 0.00527

GnomAD4 exome AF: 0.00833 AC: 12147 AN: 1458144 Hom.: 59 Cov.: 34 AF XY: 0.00815 AC XY: 5909 AN XY: 725386

African (AFR) AF: 0.00111 AC: 37 AN: 33402

American (AMR) AF: 0.00210 AC: 94 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.00241 AC: 63 AN: 26126

East Asian (EAS) AF: 0.0000756 AC: 3 AN: 39694

South Asian (SAS) AF: 0.00101 AC: 87 AN: 86164

European-Finnish (FIN) AF: 0.00323 AC: 168 AN: 52054

Middle Eastern (MID) AF: 0.00121 AC: 5 AN: 4136

European-Non Finnish (NFE) AF: 0.0101 AC: 11192 AN: 1111686

Other (OTH) AF: 0.00828 AC: 498 AN: 60172

GnomAD4 genome AF: 0.00499 AC: 760 AN: 152310 Hom.: 4 Cov.: 31 AF XY: 0.00451 AC XY: 336 AN XY: 74464

African (AFR) AF: 0.00125 AC: 52 AN: 41586

American (AMR) AF: 0.00301 AC: 46 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00115 AC: 4 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5150

South Asian (SAS) AF: 0.00269 AC: 13 AN: 4832

European-Finnish (FIN) AF: 0.00348 AC: 37 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00863 AC: 587 AN: 68028

Other (OTH) AF: 0.00284 AC: 6 AN: 2116

Alfa AF: 0.00656 Hom.: 2

Bravo AF: 0.00496

EpiCase AF: 0.00889

EpiControl AF: 0.00753

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	4	not specified (4)
-	-	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	-0.42
CADD	Benign	6.8
DANN	Benign	0.80
PhyloP100		0.11
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	polymorphism

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: rs117856830; hg19: chr16-2153619;