16-2114807-C-T

Position:

• chr16-2114807-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001009944.3(PKD1):​c.2216G>A​(p.Arg739Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.967 in 151,846 control chromosomes in the GnomAD database, including 71,015 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.97 (71015 hom., cov: 29)
  • Exomes 𝑓: 0.94 (321180 hom.)
  • Failed GnomAD Quality Control
• Consequence: PKD1 NM_001009944.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.129

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.1254682E-6).
• BP6: Variant 16-2114807-C-T is Benign according to our data. Variant chr16-2114807-C-T is described in ClinVar as [Benign]. Clinvar id is 803171.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2114807-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.983 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PKD1	NM_001009944.3	c.2216G>A	p.Arg739Gln	missense_variant	11/46	ENST00000262304.9	NP_001009944.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PKD1	ENST00000262304.9	c.2216G>A	p.Arg739Gln	missense_variant	11/46	1	NM_001009944.3	ENSP00000262304.4

Frequencies

GnomAD3 genomes AF: 0.967 AC: 146712 AN: 151736 Hom.: 70960 Cov.: 29

Gnomad AFR AF: 0.991

Gnomad AMI AF: 0.929

Gnomad AMR AF: 0.965

Gnomad ASJ AF: 0.909

Gnomad EAS AF: 0.999

Gnomad SAS AF: 0.980

Gnomad FIN AF: 0.967

Gnomad MID AF: 0.896

Gnomad NFE AF: 0.954

Gnomad OTH AF: 0.952

GnomAD3 exomes AF: 0.974 AC: 117960 AN: 121052 Hom.: 57730 AF XY: 0.975 AC XY: 63498 AN XY: 65110

Gnomad AFR exome AF: 0.995

Gnomad AMR exome AF: 0.978

Gnomad ASJ exome AF: 0.936

Gnomad EAS exome AF: 1.00

Gnomad SAS exome AF: 0.988

Gnomad FIN exome AF: 0.982

Gnomad NFE exome AF: 0.964

Gnomad OTH exome AF: 0.966

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.941 AC: 664189 AN: 705646 Hom.: 321180 Cov.: 10 AF XY: 0.944 AC XY: 345435 AN XY: 366082

Gnomad4 AFR exome AF: 0.989

Gnomad4 AMR exome AF: 0.970

Gnomad4 ASJ exome AF: 0.895

Gnomad4 EAS exome AF: 1.00

Gnomad4 SAS exome AF: 0.978

Gnomad4 FIN exome AF: 0.963

Gnomad4 NFE exome AF: 0.929

Gnomad4 OTH exome AF: 0.944

GnomAD4 genome AF: 0.967 AC: 146822 AN: 151846 Hom.: 71015 Cov.: 29 AF XY: 0.968 AC XY: 71820 AN XY: 74214

Gnomad4 AFR AF: 0.991

Gnomad4 AMR AF: 0.965

Gnomad4 ASJ AF: 0.909

Gnomad4 EAS AF: 0.999

Gnomad4 SAS AF: 0.981

Gnomad4 FIN AF: 0.967

Gnomad4 NFE AF: 0.954

Gnomad4 OTH AF: 0.952

Alfa AF: 0.959 Hom.: 15140

Bravo AF: 0.968

ExAC AF: 0.790 AC: 12122

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Polycystic kidney disease, adult type Benign:3

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 14, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jul 03, 2018	- -

not specified Benign:2

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.058
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.78
CADD	Benign	1.5
DANN	Benign	0.62
DEOGEN2	Benign	0.13	T;.
Eigen	Benign	-2.0
Eigen_PC	Benign	-1.9
FATHMM_MKL	Benign	0.0016	N
LIST_S2	Benign	0.17	T;T
MetaRNN	Benign	0.0000011	T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	-0.63	N;N
PrimateAI	Benign	0.39	T
PROVEAN	Benign	0.29	N;N
REVEL	Benign	0.036
Sift	Benign	0.72	T;T
Sift4G	Benign	0.82	T;T
Polyphen		0.0070	B;B
Vest4		0.0040
ClinPred		0.00058	T
GERP RS		-2.5
Varity_R		0.019
gMVP		0.17

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

Publications

LitVar

Other links and lift over

dbSNP: rs40433; hg19: chr16-2164808; COSMIC: COSV51910080; COSMIC: COSV51910080;