NM_001009944.3:c.5847C>T

Variant names:

• chr16-2109320-G-A
• rs80111665
• NM_001009944.3:c.5847C>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.5847C>T​(p.Ser1949Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00258 in 1,587,532 control chromosomes in the GnomAD database, including 70 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0041 (13 hom., cov: 33)
  • Exomes 𝑓: 0.0024 (57 hom.)
• Consequence: PKD1 NM_001009944.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -3.46
• Publications: 4 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=-0.9).
• BP6: Variant 16-2109320-G-A is Benign according to our data. Variant chr16-2109320-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 256983.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-3.46 with no splicing effect.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00408 (622/152350) while in subpopulation EAS AF = 0.0539 (279/5174). AF 95% confidence interval is 0.0487. There are 13 homozygotes in GnomAd4. There are 370 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 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.5847C>T	p.Ser1949Ser	synonymous	Exon 15 of 46	NP_001009944.3	P98161-1
	PKD1	NM_000296.4		c.5847C>T	p.Ser1949Ser	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.5847C>T	p.Ser1949Ser	synonymous	Exon 15 of 46	ENSP00000262304.4	P98161-1
	PKD1	ENST00000423118.5	TSL:1	c.5847C>T	p.Ser1949Ser	synonymous	Exon 15 of 46	ENSP00000399501.1	P98161-3
	PKD1	ENST00000488185.2	TSL:5	c.471-962C>T		intron	N/A	ENSP00000456672.1	H3BSE9

Frequencies

GnomAD3 genomes AF: 0.00409 AC: 622 AN: 152232 Hom.: 13 Cov.: 33

Gnomad AFR AF: 0.000362

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00464

Gnomad ASJ AF: 0.00749

Gnomad EAS AF: 0.0540

Gnomad SAS AF: 0.00290

Gnomad FIN AF: 0.0150

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000750

Gnomad OTH AF: 0.00287

GnomAD2 exomes AF: 0.00663 AC: 1518 AN: 228966 AF XY: 0.00588

Gnomad AFR exome AF: 0.000213

Gnomad AMR exome AF: 0.00329

Gnomad ASJ exome AF: 0.00435

Gnomad EAS exome AF: 0.0541

Gnomad FIN exome AF: 0.0170

Gnomad NFE exome AF: 0.000856

Gnomad OTH exome AF: 0.00677

GnomAD4 exome AF: 0.00242 AC: 3475 AN: 1435182 Hom.: 57 Cov.: 34 AF XY: 0.00236 AC XY: 1679 AN XY: 711902

African (AFR) AF: 0.000151 AC: 5 AN: 33126

American (AMR) AF: 0.00413 AC: 183 AN: 44260

Ashkenazi Jewish (ASJ) AF: 0.00440 AC: 113 AN: 25696

East Asian (EAS) AF: 0.0403 AC: 1586 AN: 39354

South Asian (SAS) AF: 0.00184 AC: 157 AN: 85310

European-Finnish (FIN) AF: 0.0154 AC: 632 AN: 41020

Middle Eastern (MID) AF: 0.000663 AC: 3 AN: 4522

European-Non Finnish (NFE) AF: 0.000414 AC: 456 AN: 1102448

Other (OTH) AF: 0.00572 AC: 340 AN: 59446

GnomAD4 genome AF: 0.00408 AC: 622 AN: 152350 Hom.: 13 Cov.: 33 AF XY: 0.00497 AC XY: 370 AN XY: 74492

African (AFR) AF: 0.000361 AC: 15 AN: 41602

American (AMR) AF: 0.00477 AC: 73 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00749 AC: 26 AN: 3470

East Asian (EAS) AF: 0.0539 AC: 279 AN: 5174

South Asian (SAS) AF: 0.00269 AC: 13 AN: 4830

European-Finnish (FIN) AF: 0.0150 AC: 159 AN: 10626

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

European-Non Finnish (NFE) AF: 0.000750 AC: 51 AN: 68020

Other (OTH) AF: 0.00284 AC: 6 AN: 2112

Alfa AF: 0.00190 Hom.: 0

Bravo AF: 0.00372

Asia WGS AF: 0.0220 AC: 77 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	PKD1-related disorder (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	-0.90
CADD	Benign	0.32
DANN	Benign	0.86
PhyloP100		-3.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.8
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs80111665; hg19: chr16-2159321; COSMIC: COSV107269481; COSMIC: COSV107269481;