NM_001009944.3:c.8237G>A

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BS1 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: 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: Benign. The variant received -12 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.
• 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

Sel.	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	P98161-1
	PKD1	NM_000296.4		c.8237G>A	p.Arg2746Gln	missense	Exon 23 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.8237G>A	p.Arg2746Gln	missense	Exon 23 of 46	ENSP00000262304.4	P98161-1
	PKD1	ENST00000423118.5	TSL:1	c.8237G>A	p.Arg2746Gln	missense	Exon 23 of 46	ENSP00000399501.1	P98161-3
	PKD1	ENST00000567946.1	TSL:5	c.296G>A	p.Arg99Gln	missense	Exon 3 of 12	ENSP00000457984.1	H3BV77

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

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;