rs1441482246

Variant names:

• chr16-2118744-G-A
• rs1441482246
• NM_001009944.3:c.461C>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM1

The NM_001009944.3(PKD1):​c.461C>T​(p.Thr154Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000013 in 1,311,582 control chromosomes in the GnomAD database, with no homozygous occurrence. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. T154T) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000013 (0 hom.)
• Consequence: PKD1 NM_001009944.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.242
• Publications: 0 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: ClinGen, Orphanet
• 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: Uncertain_significance. The variant received 2 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, 6 uncertain in NM_001009944.3

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PKD1	NM_001009944.3	c.461C>T	p.Thr154Met	missense_variant	Exon 4 of 46	ENST00000262304.9	NP_001009944.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PKD1	ENST00000262304.9	c.461C>T	p.Thr154Met	missense_variant	Exon 4 of 46	1	NM_001009944.3	ENSP00000262304.4
PKD1	ENST00000423118.5	c.461C>T	p.Thr154Met	missense_variant	Exon 4 of 46	1		ENSP00000399501.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000286 AC: 2 AN: 69988 AF XY: 0.0000281

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000706

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000130 AC: 17 AN: 1311582 Hom.: 0 Cov.: 19 AF XY: 0.0000122 AC XY: 8 AN XY: 656536

African (AFR) AF: 0.0000324 AC: 1 AN: 30874

American (AMR) AF: 0.0000249 AC: 1 AN: 40218

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24892

East Asian (EAS) AF: 0.000263 AC: 10 AN: 38082

South Asian (SAS) AF: 0.0000124 AC: 1 AN: 80618

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 35792

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3890

European-Non Finnish (NFE) AF: 0.00000200 AC: 2 AN: 1001624

Other (OTH) AF: 0.0000360 AC: 2 AN: 55592

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 23, 2017

Athena Diagnostics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.085
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	7.0
DANN	Benign	0.60
DEOGEN2	Benign	0.19	T;.
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.3
LIST_S2	Benign	0.55	T;T
M_CAP	Pathogenic	0.71	D
MetaRNN	Uncertain	0.45	T;T
MetaSVM	Benign	-0.43	T
MutationAssessor	Benign	1.9	L;L
PhyloP100		0.24
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-0.81	N;N
Sift	Benign	0.23	T;T
Sift4G	Benign	0.27	T;T
Vest4		0.15
ClinPred		0.041	T
GERP RS		-3.5
Varity_R		0.012
gMVP		0.25
Mutation Taster		=12/88	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1441482246; hg19: chr16-2168745;