16-2114754-G-T

Variant names:

• chr16-2114754-G-T
• rs775710328
• NM_001009944.3:c.2269C>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_001009944.3(PKD1):​c.2269C>A​(p.Gln757Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000835 in 1,317,836 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000083 (1 hom.)
• Consequence: PKD1 NM_001009944.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.443
• Publications: 2 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: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.10928267).

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.2269C>A	p.Gln757Lys	missense	Exon 11 of 46	NP_001009944.3	P98161-1
	PKD1	NM_000296.4		c.2269C>A	p.Gln757Lys	missense	Exon 11 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.2269C>A	p.Gln757Lys	missense	Exon 11 of 46	ENSP00000262304.4	P98161-1
	PKD1	ENST00000423118.5	TSL:1	c.2269C>A	p.Gln757Lys	missense	Exon 11 of 46	ENSP00000399501.1	P98161-3
	PKD1	ENST00000488185.2	TSL:5	c.470+2735C>A		intron	N/A	ENSP00000456672.1	H3BSE9

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000225 AC: 3 AN: 133238 AF XY: 0.0000415

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: 0.00000835 AC: 11 AN: 1317836 Hom.: 1 Cov.: 23 AF XY: 0.0000168 AC XY: 11 AN XY: 653076

African (AFR) AF: 0.00 AC: 0 AN: 30130

American (AMR) AF: 0.00 AC: 0 AN: 35566

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24762

East Asian (EAS) AF: 0.00 AC: 0 AN: 35366

South Asian (SAS) AF: 0.000141 AC: 11 AN: 77806

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33630

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3966

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1021046

Other (OTH) AF: 0.00 AC: 0 AN: 55564

GnomAD4 genome Cov.: 32

ExAC AF: 0.000134 AC: 3

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	2.9
DANN	Benign	0.64
DEOGEN2	Benign	0.18	T
Eigen	Benign	-0.84
Eigen_PC	Benign	-0.90
FATHMM_MKL	Benign	0.083	N
LIST_S2	Benign	0.42	T
M_CAP	Benign	0.059	D
MetaRNN	Benign	0.11	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		0.44
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-0.87	N
REVEL	Benign	0.069
Sift	Benign	0.31	T
Sift4G	Benign	0.54	T
Polyphen		0.36	B
Vest4		0.069
MutPred		0.42		Gain of ubiquitination at Q757 (P = 0.0198)
MVP		0.70
ClinPred		0.31	T
GERP RS		0.87
Varity_R		0.096
gMVP		0.26
Mutation Taster		=80/20	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: rs775710328; hg19: chr16-2164755;