rs201238819

Variant names:

• chr16-2104572-A-C
• rs201238819
• NM_001009944.3:c.8087T>G

Your query was ambiguous. Multiple possible variants found:

• chr16-2104572-A-C
• chr16-2104572-A-G
• chr16-2104572-A-T

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS1

The NM_001009944.3(PKD1):​c.8087T>G​(p.Leu2696Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 16/22 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. L2696F) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0015 (0 hom., cov: 20)
  • Exomes 𝑓: 0.00041 (1 hom.)
  • Failed GnomAD Quality Control
• Consequence: PKD1 NM_001009944.3 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:2
• Conservation: PhyloP100: 0.659
• Publications: 12 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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0077767074).
• BP6: Variant 16-2104572-A-C is Benign according to our data. Variant chr16-2104572-A-C is described in ClinVar as Likely_benign. ClinVar VariationId is 433983.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.0015 (219/145524) while in subpopulation AMR AF = 0.00388 (57/14680). AF 95% confidence interval is 0.00308. There are 0 homozygotes in GnomAd4. There are 107 alleles in the male GnomAd4 subpopulation. Median coverage is 20. This position passed quality control check.

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.8087T>G	p.Leu2696Arg	missense	Exon 22 of 46	NP_001009944.3	P98161-1
	PKD1	NM_000296.4		c.8087T>G	p.Leu2696Arg	missense	Exon 22 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.8087T>G	p.Leu2696Arg	missense	Exon 22 of 46	ENSP00000262304.4	P98161-1
	PKD1	ENST00000423118.5	TSL:1	c.8087T>G	p.Leu2696Arg	missense	Exon 22 of 46	ENSP00000399501.1	P98161-3
	PKD1	ENST00000567946.1	TSL:5	c.146T>G	p.Leu49Arg	missense	Exon 2 of 12	ENSP00000457984.1	H3BV77

Frequencies

GnomAD3 genomes AF: 0.00150 AC: 218 AN: 145412 Hom.: 0 Cov.: 20

Gnomad AFR AF: 0.00187

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00389

Gnomad ASJ AF: 0.00178

Gnomad EAS AF: 0.000846

Gnomad SAS AF: 0.00133

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00100

Gnomad OTH AF: 0.00300

GnomAD2 exomes AF: 0.00108 AC: 184 AN: 170576 AF XY: 0.00112

Gnomad AFR exome AF: 0.00167

Gnomad AMR exome AF: 0.00203

Gnomad ASJ exome AF: 0.00245

Gnomad EAS exome AF: 0.000145

Gnomad FIN exome AF: 0.000160

Gnomad NFE exome AF: 0.000886

Gnomad OTH exome AF: 0.00194

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.000412 AC: 596 AN: 1447962 Hom.: 1 Cov.: 30 AF XY: 0.000417 AC XY: 300 AN XY: 720112

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00145 AC: 48 AN: 33218

American (AMR) AF: 0.00174 AC: 77 AN: 44198

Ashkenazi Jewish (ASJ) AF: 0.000734 AC: 19 AN: 25892

East Asian (EAS) AF: 0.00134 AC: 53 AN: 39480

South Asian (SAS) AF: 0.000341 AC: 29 AN: 85014

European-Finnish (FIN) AF: 0.0000793 AC: 4 AN: 50416

Middle Eastern (MID) AF: 0.000729 AC: 3 AN: 4116

European-Non Finnish (NFE) AF: 0.000301 AC: 333 AN: 1105806

Other (OTH) AF: 0.000501 AC: 30 AN: 59822

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00150 AC: 219 AN: 145524 Hom.: 0 Cov.: 20 AF XY: 0.00151 AC XY: 107 AN XY: 70886

African (AFR) AF: 0.00189 AC: 74 AN: 39180

American (AMR) AF: 0.00388 AC: 57 AN: 14680

Ashkenazi Jewish (ASJ) AF: 0.00178 AC: 6 AN: 3362

East Asian (EAS) AF: 0.000848 AC: 4 AN: 4718

South Asian (SAS) AF: 0.00133 AC: 6 AN: 4524

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10178

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 278

European-Non Finnish (NFE) AF: 0.00100 AC: 66 AN: 65720

Other (OTH) AF: 0.00297 AC: 6 AN: 2018

Alfa AF: 0.000692 Hom.: 0

ExAC AF: 0.000474 AC: 54

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)
-	-	1	Polycystic kidney disease (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.043
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	4.7
DANN	Benign	0.57
DEOGEN2	Benign	0.13	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.28	N
LIST_S2	Benign	0.044	T
M_CAP	Benign	0.051	D
MetaRNN	Benign	0.0078	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	-2.2	N
PhyloP100		0.66
PrimateAI	Benign	0.43	T
PROVEAN	Benign	2.1	N
REVEL	Benign	0.25
Sift	Benign	0.89	T
Sift4G	Benign	0.93	T
Polyphen		0.0	B
Vest4		0.16
MVP		0.76
ClinPred		0.00030	T
GERP RS		-1.7
Varity_R		0.055
gMVP		0.16
Mutation Taster		=87/13	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs201238819; hg19: chr16-2154573; COSMIC: COSV51910409; COSMIC: COSV51910409;