chr16-2114807-C-T

Variant names:

• chr16-2114807-C-T
• rs40433
• NM_001009944.3:c.2216G>A

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 2P and 20B. PM5 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. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R739W) has been classified as Pathogenic.

• 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: Not reported in ClinVar
• Conservation: PhyloP100: 0.129
• Publications: 25 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.

• PM5: Other missense variant is known to change same aminoacid residue: Variant chr16-2114808-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 433952.Status of the report is criteria_provided_single_submitter, 1 stars.
• 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 VariationId is 803171.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.983 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.2216G>A	p.Arg739Gln	missense	Exon 11 of 46	NP_001009944.3	P98161-1
	PKD1	NM_000296.4		c.2216G>A	p.Arg739Gln	missense	Exon 11 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.2216G>A	p.Arg739Gln	missense	Exon 11 of 46	ENSP00000262304.4	P98161-1
	PKD1	ENST00000423118.5	TSL:1	c.2216G>A	p.Arg739Gln	missense	Exon 11 of 46	ENSP00000399501.1	P98161-3
	PKD1	ENST00000488185.2	TSL:5	c.470+2682G>A		intron	N/A	ENSP00000456672.1	H3BSE9

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

GnomAD2 exomes AF: 0.974 AC: 117960 AN: 121052 AF XY: 0.975

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 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

African (AFR) AF: 0.989 AC: 18330 AN: 18532

American (AMR) AF: 0.970 AC: 30307 AN: 31234

Ashkenazi Jewish (ASJ) AF: 0.895 AC: 16633 AN: 18592

East Asian (EAS) AF: 1.00 AC: 32579 AN: 32588

South Asian (SAS) AF: 0.978 AC: 59383 AN: 60742

European-Finnish (FIN) AF: 0.963 AC: 30673 AN: 31856

Middle Eastern (MID) AF: 0.888 AC: 2370 AN: 2668

European-Non Finnish (NFE) AF: 0.929 AC: 440825 AN: 474372

Other (OTH) AF: 0.944 AC: 33089 AN: 35062

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

African (AFR) AF: 0.991 AC: 41112 AN: 41492

American (AMR) AF: 0.965 AC: 14719 AN: 15256

Ashkenazi Jewish (ASJ) AF: 0.909 AC: 3142 AN: 3456

East Asian (EAS) AF: 0.999 AC: 5149 AN: 5152

South Asian (SAS) AF: 0.981 AC: 4717 AN: 4810

European-Finnish (FIN) AF: 0.967 AC: 10254 AN: 10608

Middle Eastern (MID) AF: 0.895 AC: 263 AN: 294

European-Non Finnish (NFE) AF: 0.954 AC: 64616 AN: 67762

Other (OTH) AF: 0.952 AC: 2003 AN: 2104

Alfa AF: 0.964 Hom.: 17402

Bravo AF: 0.968

ExAC AF: 0.790 AC: 12122

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

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
MetaRNN	Benign	0.0000011	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	-0.63	N
PhyloP100		0.13
PrimateAI	Benign	0.39	T
PROVEAN	Benign	0.29	N
REVEL	Benign	0.036
Sift	Benign	0.72	T
Sift4G	Benign	0.82	T
Polyphen		0.0070	B
Vest4		0.0040
ClinPred		0.00058	T
GERP RS		-2.5
Varity_R		0.019
gMVP		0.17
Mutation Taster		=82/18	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: rs40433; hg19: chr16-2164808; COSMIC: COSV51910080; COSMIC: COSV51910080;