16-2118021-C-A

Variant names:

• chr16-2118021-C-A
• rs199476099
• NM_001009944.3:c.971G>T

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_Moderate BP6 BS1 BS2

The NM_001009944.3(PKD1):​c.971G>T​(p.Arg324Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0032 in 1,595,092 control chromosomes in the GnomAD database, including 22 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 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. R324C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0034 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0032 (20 hom.)
• Consequence: PKD1 NM_001009944.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:2 B:7
• Conservation: PhyloP100: 0.0190
• Publications: 20 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 -11 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.08251116).
• BP6: Variant 16-2118021-C-A is Benign according to our data. Variant chr16-2118021-C-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 8205.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00336 (512/152354) while in subpopulation NFE AF = 0.00566 (385/68032). AF 95% confidence interval is 0.00519. There are 2 homozygotes in GnomAd4. There are 254 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 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.971G>T	p.Arg324Leu	missense	Exon 5 of 46	NP_001009944.3	P98161-1
	PKD1	NM_000296.4		c.971G>T	p.Arg324Leu	missense	Exon 5 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.971G>T	p.Arg324Leu	missense	Exon 5 of 46	ENSP00000262304.4	P98161-1
	PKD1	ENST00000423118.5	TSL:1	c.971G>T	p.Arg324Leu	missense	Exon 5 of 46	ENSP00000399501.1	P98161-3
	PKD1	ENST00000488185.2	TSL:5	c.56G>T	p.Arg19Leu	missense	Exon 1 of 5	ENSP00000456672.1	H3BSE9

Frequencies

GnomAD3 genomes AF: 0.00337 AC: 513 AN: 152236 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00294

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00583

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00566

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.00250 AC: 476 AN: 190410 AF XY: 0.00243

Gnomad AFR exome AF: 0.000287

Gnomad AMR exome AF: 0.000951

Gnomad ASJ exome AF: 0.00265

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00551

Gnomad NFE exome AF: 0.00416

Gnomad OTH exome AF: 0.00298

GnomAD4 exome AF: 0.00318 AC: 4585 AN: 1442738 Hom.: 20 Cov.: 33 AF XY: 0.00323 AC XY: 2323 AN XY: 718328

African (AFR) AF: 0.000300 AC: 10 AN: 33284

American (AMR) AF: 0.00135 AC: 60 AN: 44446

Ashkenazi Jewish (ASJ) AF: 0.00230 AC: 60 AN: 26046

East Asian (EAS) AF: 0.00 AC: 0 AN: 39592

South Asian (SAS) AF: 0.000151 AC: 13 AN: 85834

European-Finnish (FIN) AF: 0.00586 AC: 247 AN: 42180

Middle Eastern (MID) AF: 0.000242 AC: 1 AN: 4124

European-Non Finnish (NFE) AF: 0.00367 AC: 4062 AN: 1107478

Other (OTH) AF: 0.00221 AC: 132 AN: 59754

GnomAD4 genome AF: 0.00336 AC: 512 AN: 152354 Hom.: 2 Cov.: 32 AF XY: 0.00341 AC XY: 254 AN XY: 74502

African (AFR) AF: 0.000240 AC: 10 AN: 41580

American (AMR) AF: 0.00294 AC: 45 AN: 15312

Ashkenazi Jewish (ASJ) AF: 0.00144 AC: 5 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5174

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00583 AC: 62 AN: 10630

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

European-Non Finnish (NFE) AF: 0.00566 AC: 385 AN: 68032

Other (OTH) AF: 0.00189 AC: 4 AN: 2116

Alfa AF: 0.00419 Hom.: 1

Bravo AF: 0.00274

ESP6500AA AF: 0.000277 AC: 1

ESP6500EA AF: 0.00225 AC: 17

ExAC AF: 0.00225 AC: 261

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
1	2	1	Polycystic kidney disease, adult type (4)
-	-	2	not provided (2)
-	-	2	not specified (2)
-	-	1	PKD1-related disorder (1)
-	-	1	Polycystic kidney disease (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.14
CADD	Benign	17
DANN	Uncertain	0.99
DEOGEN2	Benign	0.29	T
Eigen	Benign	-0.47
Eigen_PC	Benign	-0.59
FATHMM_MKL	Benign	0.22	N
LIST_S2	Benign	0.80	T
MetaRNN	Benign	0.083	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		0.019
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-2.1	N
REVEL	Uncertain	0.36
Sift	Benign	0.067	T
Sift4G	Uncertain	0.033	D
Polyphen		0.87	P
Vest4		0.74
MVP		0.95
ClinPred		0.016	T
GERP RS		-0.52
PromoterAI		-0.020	Neutral
Varity_R		0.25
gMVP		0.62
Mutation Taster		=79/21	disease causing (ClinVar)

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: rs199476099; hg19: chr16-2168022;