rs886038369

Variant names:

• chr16-2135508-G-A
• rs886038369
• NM_001009944.3:c.182C>T
• PKD1 p.Pro61Leu

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_Moderate BP6 BS1

The NM_001009944.3(PKD1):​c.182C>T​(p.Pro61Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00104 in 1,170,080 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00060 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0011 (1 hom.)
• Consequence: PKD1 NM_001009944.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:3
• Conservation: PhyloP100: 0.636
• Publications: 6 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, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• 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 -7 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.19904986).
• BP6: Variant 16-2135508-G-A is Benign according to our data. Variant chr16-2135508-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 256928.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000603 (91/151034) while in subpopulation NFE AF = 0.00117 (79/67646). AF 95% confidence interval is 0.00096. There are 0 homozygotes in GnomAd4. There are 44 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.

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.182C>T	p.Pro61Leu	missense	Exon 1 of 46	NP_001009944.3	P98161-1
	PKD1	NM_000296.4		c.182C>T	p.Pro61Leu	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.182C>T	p.Pro61Leu	missense	Exon 1 of 46	ENSP00000262304.4	P98161-1
	PKD1	ENST00000423118.5	TSL:1	c.182C>T	p.Pro61Leu	missense	Exon 1 of 46	ENSP00000399501.1	P98161-3

Frequencies

GnomAD3 genomes AF: 0.000603 AC: 91 AN: 151034 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000266

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000983

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00117

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00111 AC: 1130 AN: 1019046 Hom.: 1 Cov.: 22 AF XY: 0.00112 AC XY: 537 AN XY: 479718

African (AFR) AF: 0.0000965 AC: 2 AN: 20736

American (AMR) AF: 0.00 AC: 0 AN: 6448

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 11794

East Asian (EAS) AF: 0.00 AC: 0 AN: 21398

South Asian (SAS) AF: 0.00 AC: 0 AN: 18866

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 18356

Middle Eastern (MID) AF: 0.000387 AC: 1 AN: 2582

European-Non Finnish (NFE) AF: 0.00125 AC: 1100 AN: 879630

Other (OTH) AF: 0.000688 AC: 27 AN: 39236

GnomAD4 genome AF: 0.000603 AC: 91 AN: 151034 Hom.: 0 Cov.: 31 AF XY: 0.000597 AC XY: 44 AN XY: 73736

African (AFR) AF: 0.000266 AC: 11 AN: 41302

American (AMR) AF: 0.00 AC: 0 AN: 15158

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3450

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.0000983 AC: 1 AN: 10168

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 312

European-Non Finnish (NFE) AF: 0.00117 AC: 79 AN: 67646

Other (OTH) AF: 0.00 AC: 0 AN: 2072

Alfa AF: 0.00121 Hom.: 0

Bravo AF: 0.000661

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	1	1	not specified (2)
-	1	-	Polycystic kidney disease, adult type (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.31
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.21	T
Eigen	Benign	-0.21
Eigen_PC	Benign	-0.27
FATHMM_MKL	Benign	0.71	D
LIST_S2	Benign	0.66	T
M_CAP	Pathogenic	0.62	D
MetaRNN	Benign	0.20	T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	0.69	N
PhyloP100		0.64
PrimateAI	Uncertain	0.78	T
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.080
Sift	Uncertain	0.010	D
Sift4G	Uncertain	0.026	D
PromoterAI		0.090	Neutral
Varity_R		0.091
gMVP		0.33
Mutation Taster		=79/21	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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs886038369;

hg19: chr16-2185509;