chr16-2111116-G-A

Variant names:

• chr16-2111116-G-A
• rs55840049
• NM_001009944.3:c.4051C>T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001009944.3(PKD1):​c.4051C>T​(p.Arg1351Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00096 in 1,610,818 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1351L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0047 (8 hom., cov: 33)
  • Exomes 𝑓: 0.00057 (5 hom.)
• Consequence: PKD1 NM_001009944.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:7
• Conservation: PhyloP100: 0.667
• Publications: 7 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.011341393).
• BP6: Variant 16-2111116-G-A is Benign according to our data. Variant chr16-2111116-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 225439.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00472 (719/152312) while in subpopulation AFR AF = 0.0163 (679/41570). AF 95% confidence interval is 0.0153. There are 8 homozygotes in GnomAd4. There are 348 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.4051C>T	p.Arg1351Trp	missense	Exon 15 of 46	NP_001009944.3	P98161-1
	PKD1	NM_000296.4		c.4051C>T	p.Arg1351Trp	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.4051C>T	p.Arg1351Trp	missense	Exon 15 of 46	ENSP00000262304.4	P98161-1
	PKD1	ENST00000423118.5	TSL:1	c.4051C>T	p.Arg1351Trp	missense	Exon 15 of 46	ENSP00000399501.1	P98161-3
	PKD1	ENST00000488185.2	TSL:5	c.471-2758C>T		intron	N/A	ENSP00000456672.1	H3BSE9

Frequencies

GnomAD3 genomes AF: 0.00472 AC: 719 AN: 152194 Hom.: 8 Cov.: 33

Gnomad AFR AF: 0.0164

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00150

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000964

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00383

GnomAD2 exomes AF: 0.00119 AC: 296 AN: 247814 AF XY: 0.000801

Gnomad AFR exome AF: 0.0148

Gnomad AMR exome AF: 0.000754

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00128

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000629

Gnomad OTH exome AF: 0.000496

GnomAD4 exome AF: 0.000567 AC: 827 AN: 1458506 Hom.: 5 Cov.: 36 AF XY: 0.000498 AC XY: 361 AN XY: 725606

African (AFR) AF: 0.0163 AC: 546 AN: 33416

American (AMR) AF: 0.000984 AC: 44 AN: 44702

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26110

East Asian (EAS) AF: 0.00300 AC: 119 AN: 39694

South Asian (SAS) AF: 0.0000696 AC: 6 AN: 86170

European-Finnish (FIN) AF: 0.0000384 AC: 2 AN: 52126

Middle Eastern (MID) AF: 0.00138 AC: 6 AN: 4350

European-Non Finnish (NFE) AF: 0.0000306 AC: 34 AN: 1111742

Other (OTH) AF: 0.00116 AC: 70 AN: 60196

GnomAD4 genome AF: 0.00472 AC: 719 AN: 152312 Hom.: 8 Cov.: 33 AF XY: 0.00467 AC XY: 348 AN XY: 74470

African (AFR) AF: 0.0163 AC: 679 AN: 41570

American (AMR) AF: 0.00150 AC: 23 AN: 15310

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

East Asian (EAS) AF: 0.000966 AC: 5 AN: 5174

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68022

Other (OTH) AF: 0.00379 AC: 8 AN: 2112

Alfa AF: 0.00165 Hom.: 0

Bravo AF: 0.00504

ESP6500AA AF: 0.0128 AC: 56

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00157 AC: 189

Asia WGS AF: 0.00202 AC: 7 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.000119

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.099
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.66	D
Eigen	Benign	-0.18
Eigen_PC	Benign	-0.39
FATHMM_MKL	Benign	0.11	N
LIST_S2	Uncertain	0.88	D
MetaRNN	Benign	0.011	T
MetaSVM	Benign	-0.80	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		0.67
PrimateAI	Benign	0.23	T
PROVEAN	Uncertain	-2.8	D
REVEL	Benign	0.14
Sift	Uncertain	0.020	D
Sift4G	Uncertain	0.0030	D
Polyphen		1.0	D
Vest4		0.83
MVP		0.63
ClinPred		0.025	T
GERP RS		2.4
Varity_R		0.081
gMVP		0.58
Mutation Taster		=78/22	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: rs55840049; hg19: chr16-2161117;