rs750798165

Variant names:

• chr16-2116856-T-A
• rs750798165
• NM_001009944.3:c.1583A>T

Your query was ambiguous. Multiple possible variants found:

• chr16-2116856-T-A
• chr16-2116856-T-C

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PM5

The NM_001009944.3(PKD1):​c.1583A>T​(p.Tyr528Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000029 in 1,377,574 control chromosomes in the GnomAD database, with no homozygous occurrence. 13/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y528C) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000029 (0 hom.)
• Consequence: PKD1 NM_001009944.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.13
• Publications: 8 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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr16-2116856-T-C is described in ClinVar as Pathogenic. ClinVar VariationId is 433946.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PKD1	NM_001009944.3	MANE Select	c.1583A>T	p.Tyr528Phe	missense	Exon 7 of 46	NP_001009944.3
	PKD1	NM_000296.4		c.1583A>T	p.Tyr528Phe	missense	Exon 7 of 46	NP_000287.4

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PKD1	ENST00000262304.9	TSL:1 MANE Select	c.1583A>T	p.Tyr528Phe	missense	Exon 7 of 46	ENSP00000262304.4
	PKD1	ENST00000423118.5	TSL:1	c.1583A>T	p.Tyr528Phe	missense	Exon 7 of 46	ENSP00000399501.1
	PKD1	ENST00000568591.5	TSL:2	n.514A>T		non_coding_transcript_exon	Exon 3 of 12	ENSP00000457162.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00 AC: 0 AN: 135612 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

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: 0.00000290 AC: 4 AN: 1377574 Hom.: 0 Cov.: 30 AF XY: 0.00000441 AC XY: 3 AN XY: 680826

African (AFR) AF: 0.00 AC: 0 AN: 31536

American (AMR) AF: 0.00 AC: 0 AN: 36116

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25120

East Asian (EAS) AF: 0.00 AC: 0 AN: 35924

South Asian (SAS) AF: 0.00 AC: 0 AN: 79430

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33850

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4046

European-Non Finnish (NFE) AF: 0.00000372 AC: 4 AN: 1074010

Other (OTH) AF: 0.00 AC: 0 AN: 57542

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.0000100 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	19
DANN	Benign	0.77
DEOGEN2	Benign	0.17	T
Eigen	Benign	0.082
Eigen_PC	Benign	0.027
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Uncertain	0.88	D
M_CAP	Uncertain	0.22	D
MetaRNN	Uncertain	0.71	D
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.20	N
PhyloP100		3.1
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.20
Sift	Benign	0.29	T
Sift4G	Pathogenic	0.0	D
Polyphen		0.97	D
Vest4		0.50
MutPred		0.84		Loss of phosphorylation at Y528 (P = 0.0716)
MVP		0.81
ClinPred		0.64	D
GERP RS		3.7
Varity_R		0.17
gMVP		0.72
Mutation Taster		=44/56	disease causing

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: rs750798165; hg19: chr16-2166857;