rs1490043027

Variant names:

• chr16-2105392-G-A
• rs1490043027
• NM_001009944.3:c.7946C>T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM1 PP3_Moderate

The NM_001009944.3(PKD1):​c.7946C>T​(p.Thr2649Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00000488 in 1,434,310 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000049 (0 hom.)
• Consequence: PKD1 NM_001009944.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.39
• Publications: 1 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.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 10 uncertain in NM_001009944.3
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.911

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PKD1	NM_001009944.3	c.7946C>T	p.Thr2649Ile	missense_variant	Exon 21 of 46	ENST00000262304.9	NP_001009944.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PKD1	ENST00000262304.9	c.7946C>T	p.Thr2649Ile	missense_variant	Exon 21 of 46	1	NM_001009944.3	ENSP00000262304.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000867 AC: 2 AN: 230628 AF XY: 0.0000157

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: 0.00000488 AC: 7 AN: 1434310 Hom.: 0 Cov.: 32 AF XY: 0.00000560 AC XY: 4 AN XY: 714452

African (AFR) AF: 0.00 AC: 0 AN: 31594

American (AMR) AF: 0.00 AC: 0 AN: 44678

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26038

East Asian (EAS) AF: 0.00 AC: 0 AN: 39690

South Asian (SAS) AF: 0.0000348 AC: 3 AN: 86128

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 37802

Middle Eastern (MID) AF: 0.000488 AC: 2 AN: 4102

European-Non Finnish (NFE) AF: 0.00000181 AC: 2 AN: 1104518

Other (OTH) AF: 0.00 AC: 0 AN: 59760

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Sep 27, 2016

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	0.21
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.21
CADD	Benign	19
DANN	Benign	0.97
DEOGEN2	Benign	0.32	T;.
Eigen	Benign	-0.21
Eigen_PC	Benign	-0.15
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.73	T;T
M_CAP	Pathogenic	0.35	D
MetaRNN	Pathogenic	0.91	D;D
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	1.8	L;L
PhyloP100		5.4
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	-1.9	N;N
REVEL	Benign	0.24
Sift	Benign	0.13	T;T
Sift4G	Uncertain	0.017	D;D
Polyphen		0.0090	B;B
Vest4		0.75
MutPred		0.91		Gain of MoRF binding (P = 0.0877);Gain of MoRF binding (P = 0.0877);
MVP		0.92
ClinPred		0.20	T
GERP RS		2.7
PromoterAI		0.0038	Neutral
Varity_R		0.064
gMVP		0.62
Mutation Taster		=11/89	disease causing

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: rs1490043027; hg19: chr16-2155393;