rs140869992

Variant names:

• chr16-2108569-G-A
• rs140869992
• NM_001009944.3:c.6598C>T

Your query was ambiguous. Multiple possible variants found:

• chr16-2108569-G-A
• chr16-2108569-G-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001009944.3(PKD1):​c.6598C>T​(p.Arg2200Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0137 in 1,568,720 control chromosomes in the GnomAD database, including 167 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R2200H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0090 (8 hom., cov: 33)
  • Exomes 𝑓: 0.014 (159 hom.)
• Consequence: PKD1 NM_001009944.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: 1.44
• Publications: 14 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0055719614).
• BP6: Variant 16-2108569-G-A is Benign according to our data. Variant chr16-2108569-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 256990.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00903 (1375/152308) while in subpopulation NFE AF = 0.0143 (973/67998). AF 95% confidence interval is 0.0136. There are 8 homozygotes in GnomAd4. There are 604 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 8 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.6598C>T	p.Arg2200Cys	missense	Exon 15 of 46	NP_001009944.3	P98161-1
	PKD1	NM_000296.4		c.6598C>T	p.Arg2200Cys	missense	Exon 15 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.6598C>T	p.Arg2200Cys	missense	Exon 15 of 46	ENSP00000262304.4	P98161-1
	PKD1	ENST00000423118.5	TSL:1	c.6598C>T	p.Arg2200Cys	missense	Exon 15 of 46	ENSP00000399501.1	P98161-3
	PKD1	ENST00000488185.2	TSL:5	c.471-211C>T		intron	N/A	ENSP00000456672.1	H3BSE9

Frequencies

GnomAD3 genomes AF: 0.00904 AC: 1376 AN: 152190 Hom.: 8 Cov.: 33

Gnomad AFR AF: 0.00253

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00681

Gnomad ASJ AF: 0.0245

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.0110

Gnomad FIN AF: 0.00301

Gnomad MID AF: 0.00637

Gnomad NFE AF: 0.0143

Gnomad OTH AF: 0.0100

GnomAD2 exomes AF: 0.0112 AC: 2030 AN: 180444 AF XY: 0.0115

Gnomad AFR exome AF: 0.00168

Gnomad AMR exome AF: 0.00752

Gnomad ASJ exome AF: 0.0219

Gnomad EAS exome AF: 0.000148

Gnomad FIN exome AF: 0.00379

Gnomad NFE exome AF: 0.0159

Gnomad OTH exome AF: 0.0133

GnomAD4 exome AF: 0.0142 AC: 20116 AN: 1416412 Hom.: 159 Cov.: 34 AF XY: 0.0138 AC XY: 9649 AN XY: 700358

African (AFR) AF: 0.00238 AC: 78 AN: 32710

American (AMR) AF: 0.00738 AC: 283 AN: 38368

Ashkenazi Jewish (ASJ) AF: 0.0199 AC: 506 AN: 25380

East Asian (EAS) AF: 0.0000266 AC: 1 AN: 37632

South Asian (SAS) AF: 0.0112 AC: 923 AN: 82066

European-Finnish (FIN) AF: 0.00432 AC: 210 AN: 48576

Middle Eastern (MID) AF: 0.0115 AC: 47 AN: 4086

European-Non Finnish (NFE) AF: 0.0158 AC: 17259 AN: 1089098

Other (OTH) AF: 0.0138 AC: 809 AN: 58496

GnomAD4 genome AF: 0.00903 AC: 1375 AN: 152308 Hom.: 8 Cov.: 33 AF XY: 0.00811 AC XY: 604 AN XY: 74488

African (AFR) AF: 0.00253 AC: 105 AN: 41576

American (AMR) AF: 0.00680 AC: 104 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0245 AC: 85 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5190

South Asian (SAS) AF: 0.0110 AC: 53 AN: 4832

European-Finnish (FIN) AF: 0.00301 AC: 32 AN: 10624

Middle Eastern (MID) AF: 0.00685 AC: 2 AN: 292

European-Non Finnish (NFE) AF: 0.0143 AC: 973 AN: 67998

Other (OTH) AF: 0.00946 AC: 20 AN: 2114

Alfa AF: 0.00864 Hom.: 2

Bravo AF: 0.00905

TwinsUK AF: 0.0162 AC: 60

ALSPAC AF: 0.0205 AC: 79

ESP6500AA AF: 0.00264 AC: 11

ESP6500EA AF: 0.0138 AC: 113

ExAC AF: 0.00913 AC: 1005

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	3	not provided (3)
-	-	2	Polycystic kidney disease, adult type (2)
-	-	1	Autosomal dominant polycystic kidney disease (1)
-	-	1	PKD1-related disorder (1)
-	-	1	Polycystic kidney disease (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.29	T
Eigen	Benign	-0.097
Eigen_PC	Benign	-0.28
FATHMM_MKL	Benign	0.27	N
LIST_S2	Uncertain	0.87	D
MetaRNN	Benign	0.0056	T
MetaSVM	Benign	-0.76	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		1.4
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-1.5	N
REVEL	Benign	0.23
Sift	Benign	0.046	D
Sift4G	Uncertain	0.028	D
Polyphen		1.0	D
Vest4		0.39
ClinPred		0.012	T
GERP RS		3.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Varity_R		0.087
gMVP		0.50
Mutation Taster		=73/27	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: rs140869992; hg19: chr16-2158570; COSMIC: COSV51914844; COSMIC: COSV51914844;