16-2103820-C-T

Variant names:

• chr16-2103820-C-T
• rs1800569
• NM_001009944.3:c.8237G>A

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BS1_Supporting BS2

The NM_001009944.3(PKD1):​c.8237G>A​(p.Arg2746Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000183 in 1,608,100 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R2746W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00016 (0 hom., cov: 30)
  • Exomes 𝑓: 0.00019 (2 hom.)
• Consequence: PKD1 NM_001009944.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 2.70
• Publications: 4 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: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.024872541).
• BS1: Variant frequency is greater than expected in population sas. GnomAdExome4 allele frequency = 0.000185 (270/1457472) while in subpopulation SAS AF = 0.00116 (100/86138). AF 95% confidence interval is 0.000976. There are 2 homozygotes in GnomAdExome4. There are 143 alleles in the male GnomAdExome4 subpopulation. Median coverage is 34. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAdExome4 at 2 AD,AR gene

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.8237G>A	p.Arg2746Gln	missense	Exon 23 of 46	NP_001009944.3
	PKD1	NM_000296.4		c.8237G>A	p.Arg2746Gln	missense	Exon 23 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.8237G>A	p.Arg2746Gln	missense	Exon 23 of 46	ENSP00000262304.4
	PKD1	ENST00000423118.5	TSL:1	c.8237G>A	p.Arg2746Gln	missense	Exon 23 of 46	ENSP00000399501.1
	PKD1	ENST00000567946.1	TSL:5	c.296G>A	p.Arg99Gln	missense	Exon 3 of 12	ENSP00000457984.1

Frequencies

GnomAD3 genomes AF: 0.000159 AC: 24 AN: 150510 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.000147

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000659

Gnomad ASJ AF: 0.000868

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00106

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.000484

GnomAD2 exomes AF: 0.000296 AC: 73 AN: 246822 AF XY: 0.000253

Gnomad AFR exome AF: 0.000129

Gnomad AMR exome AF: 0.000290

Gnomad ASJ exome AF: 0.000805

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000117

Gnomad OTH exome AF: 0.000497

GnomAD4 exome AF: 0.000185 AC: 270 AN: 1457472 Hom.: 2 Cov.: 34 AF XY: 0.000197 AC XY: 143 AN XY: 725038

African (AFR) AF: 0.0000300 AC: 1 AN: 33388

American (AMR) AF: 0.000179 AC: 8 AN: 44692

Ashkenazi Jewish (ASJ) AF: 0.00115 AC: 30 AN: 26120

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39694

South Asian (SAS) AF: 0.00116 AC: 100 AN: 86138

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52026

Middle Eastern (MID) AF: 0.000483 AC: 2 AN: 4138

European-Non Finnish (NFE) AF: 0.0000990 AC: 110 AN: 1111124

Other (OTH) AF: 0.000299 AC: 18 AN: 60152

GnomAD4 genome AF: 0.000159 AC: 24 AN: 150628 Hom.: 0 Cov.: 30 AF XY: 0.000136 AC XY: 10 AN XY: 73508

African (AFR) AF: 0.000147 AC: 6 AN: 40922

American (AMR) AF: 0.0000658 AC: 1 AN: 15192

Ashkenazi Jewish (ASJ) AF: 0.000868 AC: 3 AN: 3458

East Asian (EAS) AF: 0.00 AC: 0 AN: 4934

South Asian (SAS) AF: 0.00106 AC: 5 AN: 4712

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10514

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.000118 AC: 8 AN: 67608

Other (OTH) AF: 0.000479 AC: 1 AN: 2086

Alfa AF: 0.000153 Hom.: 0

Bravo AF: 0.000144

ESP6500AA AF: 0.000230 AC: 1

ESP6500EA AF: 0.000234 AC: 2

ExAC AF: 0.000391 AC: 47

EpiCase AF: 0.000218

EpiControl AF: 0.000119

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	2	-	not provided (2)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	14
DANN	Benign	0.97
DEOGEN2	Benign	0.17	T
Eigen	Benign	-0.71
Eigen_PC	Benign	-0.74
FATHMM_MKL	Benign	0.39	N
LIST_S2	Benign	0.63	T
M_CAP	Benign	0.063	D
MetaRNN	Benign	0.025	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N
PhyloP100		2.7
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-0.30	N
REVEL	Benign	0.081
Sift	Benign	0.30	T
Sift4G	Benign	0.081	T
Polyphen		0.90	P
Vest4		0.30
MVP		0.59
ClinPred		0.022	T
GERP RS		1.1
Varity_R		0.026
gMVP		0.29
Mutation Taster		=64/36	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: rs1800569; hg19: chr16-2153821;