rs200168879

Variant names:

• chr16-2103394-C-T
• rs200168879
• NM_001009944.3:c.8663G>A

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BP6

The NM_001009944.3(PKD1):​c.8663G>A​(p.Arg2888His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000235 in 1,599,800 control chromosomes in the GnomAD database, including 1 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R2888C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00027 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00023 (1 hom.)
• Consequence: PKD1 NM_001009944.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:2
• Conservation: PhyloP100: -0.566
• 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 -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.045871526).
• BP6: Variant 16-2103394-C-T is Benign according to our data. Variant chr16-2103394-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 423287.

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.8663G>A	p.Arg2888His	missense	Exon 23 of 46	NP_001009944.3	P98161-1
	PKD1	NM_000296.4		c.8663G>A	p.Arg2888His	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.8663G>A	p.Arg2888His	missense	Exon 23 of 46	ENSP00000262304.4	P98161-1
	PKD1	ENST00000423118.5	TSL:1	c.8663G>A	p.Arg2888His	missense	Exon 23 of 46	ENSP00000399501.1	P98161-3
	PKD1	ENST00000480227.5	TSL:1	n.400G>A		non_coding_transcript_exon	Exon 1 of 8

Frequencies

GnomAD3 genomes AF: 0.000269 AC: 41 AN: 152188 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000720

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000579

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000309

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000192 AC: 45 AN: 234030 AF XY: 0.000224

Gnomad AFR exome AF: 0.000141

Gnomad AMR exome AF: 0.000145

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000507

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000232

Gnomad OTH exome AF: 0.000340

GnomAD4 exome AF: 0.000231 AC: 335 AN: 1447612 Hom.: 1 Cov.: 34 AF XY: 0.000254 AC XY: 183 AN XY: 720674

African (AFR) AF: 0.000180 AC: 6 AN: 33392

American (AMR) AF: 0.000179 AC: 8 AN: 44688

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26060

East Asian (EAS) AF: 0.000176 AC: 7 AN: 39688

South Asian (SAS) AF: 0.000139 AC: 12 AN: 86150

European-Finnish (FIN) AF: 0.0000476 AC: 2 AN: 42024

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4136

European-Non Finnish (NFE) AF: 0.000250 AC: 278 AN: 1111368

Other (OTH) AF: 0.000366 AC: 22 AN: 60106

GnomAD4 genome AF: 0.000269 AC: 41 AN: 152188 Hom.: 0 Cov.: 31 AF XY: 0.000202 AC XY: 15 AN XY: 74342

African (AFR) AF: 0.000145 AC: 6 AN: 41454

American (AMR) AF: 0.000720 AC: 11 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.000579 AC: 3 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10630

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000309 AC: 21 AN: 68020

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.000378 Hom.: 0

Bravo AF: 0.000314

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000120 AC: 1

ExAC AF: 0.000110 AC: 13

EpiCase AF: 0.000273

EpiControl AF: 0.000237

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	2	1	not provided (3)
-	-	1	Inborn genetic diseases (1)
-	1	-	Polycystic kidney disease, adult type (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.065
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.67
CADD	Benign	0.92
DANN	Benign	0.83
DEOGEN2	Benign	0.20	T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.015	N
LIST_S2	Benign	0.46	T
M_CAP	Benign	0.023	T
MetaRNN	Benign	0.046	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.69	N
PhyloP100		-0.57
PrimateAI	Benign	0.22	T
PROVEAN	Benign	-0.90	N
REVEL	Benign	0.0060
Sift	Benign	0.24	T
Sift4G	Benign	0.074	T
Polyphen		0.010	B
Vest4		0.23
MVP		0.35
ClinPred		0.0064	T
GERP RS		-5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.013
gMVP		0.31
Mutation Taster		=68/32	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: rs200168879; hg19: chr16-2153395; COSMIC: COSV51918456; COSMIC: COSV51918456;