16-2097499-C-G

Variant names:

• chr16-2097499-C-G
• rs61747420
• NM_001009944.3:c.10225G>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001009944.3(PKD1):​c.10225G>C​(p.Val3409Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00759 in 1,601,874 control chromosomes in the GnomAD database, including 807 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.039 (424 hom., cov: 33)
  • Exomes 𝑓: 0.0042 (383 hom.)
• Consequence: PKD1 NM_001009944.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 0.115
• Publications: 5 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=0.0040228367).
• BP6: Variant 16-2097499-C-G is Benign according to our data. Variant chr16-2097499-C-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 256886.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.133 is higher than 0.05.

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.10225G>C	p.Val3409Leu	missense	Exon 33 of 46	NP_001009944.3	P98161-1
	PKD1	NM_000296.4		c.10222G>C	p.Val3408Leu	missense	Exon 33 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.10225G>C	p.Val3409Leu	missense	Exon 33 of 46	ENSP00000262304.4	P98161-1
	PKD1	ENST00000423118.5	TSL:1	c.10222G>C	p.Val3408Leu	missense	Exon 33 of 46	ENSP00000399501.1	P98161-3
	PKD1	ENST00000487932.5	TSL:5	n.*1418G>C		non_coding_transcript_exon	Exon 20 of 30	ENSP00000457132.1	H3BTE0

Frequencies

GnomAD3 genomes AF: 0.0394 AC: 5995 AN: 152214 Hom.: 425 Cov.: 33

Gnomad AFR AF: 0.136

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0156

Gnomad ASJ AF: 0.000864

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000808

Gnomad OTH AF: 0.0349

GnomAD2 exomes AF: 0.0107 AC: 2549 AN: 237256 AF XY: 0.00763

Gnomad AFR exome AF: 0.145

Gnomad AMR exome AF: 0.00837

Gnomad ASJ exome AF: 0.00102

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000696

Gnomad NFE exome AF: 0.000541

Gnomad OTH exome AF: 0.00352

GnomAD4 exome AF: 0.00424 AC: 6139 AN: 1449542 Hom.: 383 Cov.: 33 AF XY: 0.00358 AC XY: 2586 AN XY: 721690

African (AFR) AF: 0.141 AC: 4721 AN: 33416

American (AMR) AF: 0.00931 AC: 416 AN: 44704

Ashkenazi Jewish (ASJ) AF: 0.000881 AC: 23 AN: 26116

East Asian (EAS) AF: 0.00 AC: 0 AN: 39692

South Asian (SAS) AF: 0.000128 AC: 11 AN: 86176

European-Finnish (FIN) AF: 0.0000465 AC: 2 AN: 42992

Middle Eastern (MID) AF: 0.00667 AC: 30 AN: 4500

European-Non Finnish (NFE) AF: 0.000322 AC: 358 AN: 1111794

Other (OTH) AF: 0.00961 AC: 578 AN: 60152

GnomAD4 genome AF: 0.0395 AC: 6015 AN: 152332 Hom.: 424 Cov.: 33 AF XY: 0.0377 AC XY: 2808 AN XY: 74484

African (AFR) AF: 0.136 AC: 5639 AN: 41558

American (AMR) AF: 0.0155 AC: 238 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.000864 AC: 3 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.000621 AC: 3 AN: 4828

European-Finnish (FIN) AF: 0.0000941 AC: 1 AN: 10632

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.000808 AC: 55 AN: 68030

Other (OTH) AF: 0.0345 AC: 73 AN: 2114

Alfa AF: 0.0160 Hom.: 25

Bravo AF: 0.0452

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.124 AC: 543

ESP6500EA AF: 0.000704 AC: 6

ExAC AF: 0.0124 AC: 1494

Asia WGS AF: 0.00606 AC: 21 AN: 3478

EpiCase AF: 0.000763

EpiControl AF: 0.000771

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)
-	-	1	Polycystic kidney disease (1)
-	-	1	Polycystic kidney disease, adult type (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.70	T
BayesDel_noAF	Benign	-0.65
CADD	Benign	7.9
DANN	Benign	0.81
DEOGEN2	Benign	0.20	T
Eigen	Benign	-0.58
Eigen_PC	Benign	-0.59
FATHMM_MKL	Benign	0.21	N
LIST_S2	Benign	0.69	T
MetaRNN	Benign	0.0040	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.9	L
PhyloP100		0.12
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.043
Sift	Benign	0.31	T
Sift4G	Uncertain	0.049	D
Polyphen		0.021	B
Vest4		0.17
MutPred		0.36		Loss of sheet (P = 0.0357)
ClinPred		0.0024	T
GERP RS		2.2
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.0
Varity_R		0.031
gMVP		0.15
Mutation Taster		=96/4	polymorphism (auto)

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: rs61747420; hg19: chr16-2147500;