rs141101590

Variant names:

• chr16-2099737-G-A
• rs141101590
• NM_001009944.3:c.9957C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001009944.3(PKD1):​c.9957C>T​(p.Ser3319Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0037 in 1,557,476 control chromosomes in the GnomAD database, including 14 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0037 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0037 (13 hom.)
• Consequence: PKD1 NM_001009944.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -0.734
• Publications: 1 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=-0.86).
• BP6: Variant 16-2099737-G-A is Benign according to our data. Variant chr16-2099737-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 257047.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.734 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00366 (557/152342) while in subpopulation NFE AF = 0.00443 (301/68022). AF 95% confidence interval is 0.00401. There are 1 homozygotes in GnomAd4. There are 299 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 13 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.9957C>T	p.Ser3319Ser	synonymous	Exon 30 of 46	NP_001009944.3	P98161-1
	PKD1	NM_000296.4		c.9957C>T	p.Ser3319Ser	synonymous	Exon 30 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.9957C>T	p.Ser3319Ser	synonymous	Exon 30 of 46	ENSP00000262304.4	P98161-1
	PKD1	ENST00000423118.5	TSL:1	c.9957C>T	p.Ser3319Ser	synonymous	Exon 30 of 46	ENSP00000399501.1	P98161-3
	PKD1	ENST00000480227.5	TSL:1	n.1694C>T		non_coding_transcript_exon	Exon 8 of 8

Frequencies

GnomAD3 genomes AF: 0.00366 AC: 557 AN: 152224 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000772

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00216

Gnomad ASJ AF: 0.00403

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.0155

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00442

Gnomad OTH AF: 0.00478

GnomAD2 exomes AF: 0.00341 AC: 489 AN: 143472 AF XY: 0.00328

Gnomad AFR exome AF: 0.000876

Gnomad AMR exome AF: 0.00224

Gnomad ASJ exome AF: 0.00434

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0149

Gnomad NFE exome AF: 0.00390

Gnomad OTH exome AF: 0.00309

GnomAD4 exome AF: 0.00371 AC: 5212 AN: 1405134 Hom.: 13 Cov.: 27 AF XY: 0.00359 AC XY: 2497 AN XY: 695876

African (AFR) AF: 0.000561 AC: 18 AN: 32070

American (AMR) AF: 0.00202 AC: 77 AN: 38048

Ashkenazi Jewish (ASJ) AF: 0.00387 AC: 98 AN: 25350

East Asian (EAS) AF: 0.0000270 AC: 1 AN: 36976

South Asian (SAS) AF: 0.000890 AC: 72 AN: 80922

European-Finnish (FIN) AF: 0.0136 AC: 620 AN: 45554

Middle Eastern (MID) AF: 0.000736 AC: 3 AN: 4076

European-Non Finnish (NFE) AF: 0.00379 AC: 4110 AN: 1083802

Other (OTH) AF: 0.00365 AC: 213 AN: 58336

GnomAD4 genome AF: 0.00366 AC: 557 AN: 152342 Hom.: 1 Cov.: 32 AF XY: 0.00401 AC XY: 299 AN XY: 74490

African (AFR) AF: 0.000769 AC: 32 AN: 41588

American (AMR) AF: 0.00216 AC: 33 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00403 AC: 14 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4830

European-Finnish (FIN) AF: 0.0155 AC: 165 AN: 10626

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

European-Non Finnish (NFE) AF: 0.00443 AC: 301 AN: 68022

Other (OTH) AF: 0.00473 AC: 10 AN: 2116

Alfa AF: 0.00531 Hom.: 0

Bravo AF: 0.00253

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	3	not specified (3)
-	-	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	-0.86
CADD	Benign	0.24
DANN	Benign	0.70
PhyloP100		-0.73
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: rs141101590; hg19: chr16-2149738; COSMIC: COSV99238415; COSMIC: COSV99238415;