rs560049593

Variant names:

• chr16-2135583-G-T
• rs560049593
• NM_001009944.3:c.107C>A

Your query was ambiguous. Multiple possible variants found:

• chr16-2135583-G-T
• chr16-2135583-G-A

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001009944.3(PKD1):​c.107C>A​(p.Pro36His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0219 in 1,068,452 control chromosomes in the GnomAD database, including 292 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.016 (40 hom., cov: 31)
  • Exomes 𝑓: 0.023 (252 hom.)
• Consequence: PKD1 NM_001009944.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 0.708
• Publications: 10 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 -18 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 11 uncertain in NM_001009944.3
• BP4: Computational evidence support a benign effect (MetaRNN=0.010966539).
• BP6: Variant 16-2135583-G-T is Benign according to our data. Variant chr16-2135583-G-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 256895.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0165 (2436/147704) while in subpopulation NFE AF = 0.0227 (1505/66194). AF 95% confidence interval is 0.0218. There are 40 homozygotes in GnomAd4. There are 1217 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 40 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.107C>A	p.Pro36His	missense	Exon 1 of 46	NP_001009944.3	P98161-1
	PKD1	NM_000296.4		c.107C>A	p.Pro36His	missense	Exon 1 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.107C>A	p.Pro36His	missense	Exon 1 of 46	ENSP00000262304.4	P98161-1
	PKD1	ENST00000423118.5	TSL:1	c.107C>A	p.Pro36His	missense	Exon 1 of 46	ENSP00000399501.1	P98161-3

Frequencies

GnomAD3 genomes AF: 0.0165 AC: 2436 AN: 147602 Hom.: 40 Cov.: 31

Gnomad AFR AF: 0.00481

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0127

Gnomad ASJ AF: 0.0103

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00249

Gnomad FIN AF: 0.0527

Gnomad MID AF: 0.0160

Gnomad NFE AF: 0.0227

Gnomad OTH AF: 0.0113

GnomAD4 exome AF: 0.0228 AC: 20963 AN: 920748 Hom.: 252 Cov.: 28 AF XY: 0.0227 AC XY: 9785 AN XY: 430858

African (AFR) AF: 0.00287 AC: 51 AN: 17798

American (AMR) AF: 0.00891 AC: 31 AN: 3478

Ashkenazi Jewish (ASJ) AF: 0.0135 AC: 108 AN: 8022

East Asian (EAS) AF: 0.000188 AC: 2 AN: 10614

South Asian (SAS) AF: 0.00144 AC: 26 AN: 18022

European-Finnish (FIN) AF: 0.0464 AC: 423 AN: 9110

Middle Eastern (MID) AF: 0.00862 AC: 18 AN: 2088

European-Non Finnish (NFE) AF: 0.0241 AC: 19722 AN: 818894

Other (OTH) AF: 0.0178 AC: 582 AN: 32722

GnomAD4 genome AF: 0.0165 AC: 2436 AN: 147704 Hom.: 40 Cov.: 31 AF XY: 0.0169 AC XY: 1217 AN XY: 71970

African (AFR) AF: 0.00479 AC: 197 AN: 41110

American (AMR) AF: 0.0127 AC: 189 AN: 14874

Ashkenazi Jewish (ASJ) AF: 0.0103 AC: 35 AN: 3398

East Asian (EAS) AF: 0.00 AC: 0 AN: 5134

South Asian (SAS) AF: 0.00249 AC: 12 AN: 4822

European-Finnish (FIN) AF: 0.0527 AC: 470 AN: 8912

Middle Eastern (MID) AF: 0.0172 AC: 5 AN: 290

European-Non Finnish (NFE) AF: 0.0227 AC: 1505 AN: 66194

Other (OTH) AF: 0.0112 AC: 23 AN: 2060

Alfa AF: 0.00605 Hom.: 1

Bravo AF: 0.0137

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	2	not provided (2)
-	-	1	Autosomal dominant polycystic kidney disease (1)
-	-	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
AlphaMissense	Benign	0.26
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	21
DANN	Benign	0.83
DEOGEN2	Benign	0.18	T
Eigen	Benign	-0.36
Eigen_PC	Benign	-0.48
FATHMM_MKL	Benign	0.084	N
LIST_S2	Benign	0.45	T
M_CAP	Pathogenic	0.32	D
MetaRNN	Benign	0.011	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.34	N
PhyloP100		0.71
PrimateAI	Uncertain	0.78	T
PROVEAN	Benign	-0.65	N
REVEL	Benign	0.083
Sift	Benign	0.13	T
Sift4G	Pathogenic	0.0	D
Polyphen		0.99	D
Vest4		0.28
MVP		0.41
ClinPred		0.25	T
GERP RS		2.1
PromoterAI		0.016	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.3
Varity_R		0.11
gMVP		0.32
Mutation Taster		=92/8	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: rs560049593; hg19: chr16-2185584;