rs551353498

Variant names:

• chr16-2119356-G-A
• rs551353498
• NM_001009944.3:c.238C>T

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.238C>T​(p.Arg80Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000498 in 1,464,496 control chromosomes in the GnomAD database, including 14 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R80Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00024 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00053 (14 hom.)
• Consequence: PKD1 NM_001009944.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 1.41
• Publications: 4 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: ClinGen, Orphanet
• 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

ENSG00000260447 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -18 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 4 benign, 7 uncertain in NM_001009944.3
• BP4: Computational evidence support a benign effect (MetaRNN=0.0040474236).
• BP6: Variant 16-2119356-G-A is Benign according to our data. Variant chr16-2119356-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 586259.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000236 (36/152310) while in subpopulation SAS AF = 0.0056 (27/4824). AF 95% confidence interval is 0.00395. There are 0 homozygotes in GnomAd4. There are 23 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 14 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.238C>T	p.Arg80Trp	missense	Exon 2 of 46	NP_001009944.3
	PKD1	NM_000296.4		c.238C>T	p.Arg80Trp	missense	Exon 2 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.238C>T	p.Arg80Trp	missense	Exon 2 of 46	ENSP00000262304.4
	PKD1	ENST00000423118.5	TSL:1	c.238C>T	p.Arg80Trp	missense	Exon 2 of 46	ENSP00000399501.1
	ENSG00000260447	ENST00000562027.1	TSL:5	n.150G>A		non_coding_transcript_exon	Exon 1 of 2

Frequencies

GnomAD3 genomes AF: 0.000263 AC: 40 AN: 152192 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00642

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.00158 AC: 216 AN: 136402 AF XY: 0.00219

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000409

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000189

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000183

Gnomad OTH exome AF: 0.000483

GnomAD4 exome AF: 0.000528 AC: 693 AN: 1312186 Hom.: 14 Cov.: 22 AF XY: 0.000781 AC XY: 509 AN XY: 651462

African (AFR) AF: 0.0000995 AC: 3 AN: 30150

American (AMR) AF: 0.0000281 AC: 1 AN: 35630

Ashkenazi Jewish (ASJ) AF: 0.0000404 AC: 1 AN: 24768

East Asian (EAS) AF: 0.0000565 AC: 2 AN: 35388

South Asian (SAS) AF: 0.00780 AC: 606 AN: 77706

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33816

Middle Eastern (MID) AF: 0.00102 AC: 4 AN: 3918

European-Non Finnish (NFE) AF: 0.0000394 AC: 40 AN: 1015482

Other (OTH) AF: 0.000651 AC: 36 AN: 55328

GnomAD4 genome AF: 0.000236 AC: 36 AN: 152310 Hom.: 0 Cov.: 32 AF XY: 0.000309 AC XY: 23 AN XY: 74470

African (AFR) AF: 0.0000240 AC: 1 AN: 41580

American (AMR) AF: 0.000131 AC: 2 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

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

South Asian (SAS) AF: 0.00560 AC: 27 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10630

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

European-Non Finnish (NFE) AF: 0.0000735 AC: 5 AN: 68026

Other (OTH) AF: 0.000473 AC: 1 AN: 2116

Alfa AF: 0.0000854 Hom.: 0

Bravo AF: 0.0000869

ExAC AF: 0.00271 AC: 93

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.087
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.21	T
Eigen	Benign	0.010
Eigen_PC	Benign	-0.082
FATHMM_MKL	Benign	0.24	N
LIST_S2	Benign	0.82	T
MetaRNN	Benign	0.0040	T
MetaSVM	Benign	-0.86	T
MutationAssessor	Benign	1.6	L
PhyloP100		1.4
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-1.8	N
REVEL	Benign	0.12
Sift	Uncertain	0.015	D
Sift4G	Uncertain	0.012	D
Polyphen		0.90	P
Vest4		0.19
MutPred		0.51		Gain of catalytic residue at L78 (P = 0.0698)
MVP		0.64
ClinPred		0.060	T
GERP RS		3.2
Varity_R		0.088
gMVP		0.46
Mutation Taster		=95/5	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs551353498; hg19: chr16-2169357; COSMIC: COSV51909791; COSMIC: COSV51909791;