rs149151043

Variant names:

• chr16-2103617-C-T
• rs149151043
• NM_001009944.3:c.8440G>A

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001009944.3(PKD1):​c.8440G>A​(p.Gly2814Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00735 in 1,610,450 control chromosomes in the GnomAD database, including 62 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. G2814G) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0062 (5 hom., cov: 31)
  • Exomes 𝑓: 0.0075 (57 hom.)
• Consequence: PKD1 NM_001009944.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 1.55
• Publications: 11 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 -18 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 6 uncertain in NM_001009944.3
• BP4: Computational evidence support a benign effect (MetaRNN=0.0081606805).
• BP6: Variant 16-2103617-C-T is Benign according to our data. Variant chr16-2103617-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 257021.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 = 0.0062 (944/152302) while in subpopulation NFE AF = 0.00859 (584/68018). AF 95% confidence interval is 0.00801. There are 5 homozygotes in GnomAd4. There are 495 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 5 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.8440G>A	p.Gly2814Arg	missense	Exon 23 of 46	NP_001009944.3	P98161-1
	PKD1	NM_000296.4		c.8440G>A	p.Gly2814Arg	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.8440G>A	p.Gly2814Arg	missense	Exon 23 of 46	ENSP00000262304.4	P98161-1
	PKD1	ENST00000423118.5	TSL:1	c.8440G>A	p.Gly2814Arg	missense	Exon 23 of 46	ENSP00000399501.1	P98161-3
	PKD1	ENST00000480227.5	TSL:1	n.177G>A		non_coding_transcript_exon	Exon 1 of 8

Frequencies

GnomAD3 genomes AF: 0.00621 AC: 945 AN: 152184 Hom.: 5 Cov.: 31

Gnomad AFR AF: 0.00125

Gnomad AMI AF: 0.00439

Gnomad AMR AF: 0.00720

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.0171

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00858

Gnomad OTH AF: 0.00525

GnomAD2 exomes AF: 0.00611 AC: 1520 AN: 248758 AF XY: 0.00605

Gnomad AFR exome AF: 0.00163

Gnomad AMR exome AF: 0.00417

Gnomad ASJ exome AF: 0.000401

Gnomad EAS exome AF: 0.000491

Gnomad FIN exome AF: 0.0175

Gnomad NFE exome AF: 0.00818

Gnomad OTH exome AF: 0.00659

GnomAD4 exome AF: 0.00747 AC: 10891 AN: 1458148 Hom.: 57 Cov.: 34 AF XY: 0.00714 AC XY: 5178 AN XY: 725392

African (AFR) AF: 0.00105 AC: 35 AN: 33402

American (AMR) AF: 0.00490 AC: 219 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.000421 AC: 11 AN: 26126

East Asian (EAS) AF: 0.000302 AC: 12 AN: 39694

South Asian (SAS) AF: 0.000197 AC: 17 AN: 86164

European-Finnish (FIN) AF: 0.0166 AC: 862 AN: 52048

Middle Eastern (MID) AF: 0.00290 AC: 12 AN: 4136

European-Non Finnish (NFE) AF: 0.00841 AC: 9345 AN: 1111692

Other (OTH) AF: 0.00628 AC: 378 AN: 60176

GnomAD4 genome AF: 0.00620 AC: 944 AN: 152302 Hom.: 5 Cov.: 31 AF XY: 0.00665 AC XY: 495 AN XY: 74456

African (AFR) AF: 0.00123 AC: 51 AN: 41584

American (AMR) AF: 0.00719 AC: 110 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5148

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4830

European-Finnish (FIN) AF: 0.0171 AC: 182 AN: 10624

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00859 AC: 584 AN: 68018

Other (OTH) AF: 0.00520 AC: 11 AN: 2116

Alfa AF: 0.00445 Hom.: 0

Bravo AF: 0.00544

TwinsUK AF: 0.00836 AC: 31

ALSPAC AF: 0.0106 AC: 41

ESP6500AA AF: 0.00137 AC: 6

ESP6500EA AF: 0.00828 AC: 71

ExAC AF: 0.00553 AC: 665

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	3	not specified (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	0.14
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.31	T
Eigen	Uncertain	0.25
Eigen_PC	Uncertain	0.27
FATHMM_MKL	Benign	0.54	D
LIST_S2	Benign	0.62	T
MetaRNN	Benign	0.0082	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.8	L
PhyloP100		1.5
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-2.2	N
REVEL	Benign	0.17
Sift	Benign	0.072	T
Sift4G	Uncertain	0.020	D
Polyphen		0.99	D
Vest4		0.63
MutPred		0.48		Loss of catalytic residue at G2814 (P = 0.021)
MVP		0.74
ClinPred		0.013	T
GERP RS		3.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.068
gMVP		0.56
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: rs149151043; hg19: chr16-2153618; COSMIC: COSV99032366; COSMIC: COSV99032366;