rs200509641

Variant names:

• chr16-2104548-G-A
• rs200509641
• NM_001009944.3:c.8111C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001009944.3(PKD1):​c.8111C>T​(p.Ala2704Val) variant causes a missense change. The variant allele was found at a frequency of 0.000896 in 1,589,016 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/22 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. A2704T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00066 (0 hom., cov: 20)
  • Exomes 𝑓: 0.00092 (10 hom.)
• Consequence: PKD1 NM_001009944.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 4.06
• Publications: 5 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008843273).
• BP6: Variant 16-2104548-G-A is Benign according to our data. Variant chr16-2104548-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 440103.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 = 0.00066 (99/150012) while in subpopulation SAS AF = 0.00319 (15/4708). AF 95% confidence interval is 0.00196. There are 0 homozygotes in GnomAd4. There are 52 alleles in the male GnomAd4 subpopulation. Median coverage is 20. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 10 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.8111C>T	p.Ala2704Val	missense	Exon 22 of 46	NP_001009944.3	P98161-1
	PKD1	NM_000296.4		c.8111C>T	p.Ala2704Val	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.8111C>T	p.Ala2704Val	missense	Exon 22 of 46	ENSP00000262304.4	P98161-1
	PKD1	ENST00000423118.5	TSL:1	c.8111C>T	p.Ala2704Val	missense	Exon 22 of 46	ENSP00000399501.1	P98161-3
	PKD1	ENST00000567946.1	TSL:5	c.170C>T	p.Ala57Val	missense	Exon 2 of 12	ENSP00000457984.1	H3BV77

Frequencies

GnomAD3 genomes AF: 0.000660 AC: 99 AN: 149894 Hom.: 0 Cov.: 20

Gnomad AFR AF: 0.000347

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000530

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000202

Gnomad SAS AF: 0.00318

Gnomad FIN AF: 0.00171

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.000548

Gnomad OTH AF: 0.000969

GnomAD2 exomes AF: 0.00142 AC: 223 AN: 156602 AF XY: 0.00177

Gnomad AFR exome AF: 0.000121

Gnomad AMR exome AF: 0.000274

Gnomad ASJ exome AF: 0.000355

Gnomad EAS exome AF: 0.000324

Gnomad FIN exome AF: 0.000809

Gnomad NFE exome AF: 0.00105

Gnomad OTH exome AF: 0.00204

GnomAD4 exome AF: 0.000920 AC: 1324 AN: 1439004 Hom.: 10 Cov.: 30 AF XY: 0.00113 AC XY: 806 AN XY: 714798

African (AFR) AF: 0.000423 AC: 14 AN: 33068

American (AMR) AF: 0.000442 AC: 19 AN: 43012

Ashkenazi Jewish (ASJ) AF: 0.000233 AC: 6 AN: 25718

East Asian (EAS) AF: 0.000408 AC: 16 AN: 39192

South Asian (SAS) AF: 0.00538 AC: 450 AN: 83660

European-Finnish (FIN) AF: 0.00166 AC: 82 AN: 49452

Middle Eastern (MID) AF: 0.00950 AC: 39 AN: 4106

European-Non Finnish (NFE) AF: 0.000546 AC: 601 AN: 1101336

Other (OTH) AF: 0.00163 AC: 97 AN: 59460

GnomAD4 genome AF: 0.000660 AC: 99 AN: 150012 Hom.: 0 Cov.: 20 AF XY: 0.000710 AC XY: 52 AN XY: 73196

African (AFR) AF: 0.000346 AC: 14 AN: 40474

American (AMR) AF: 0.000529 AC: 8 AN: 15116

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3454

East Asian (EAS) AF: 0.000202 AC: 1 AN: 4948

South Asian (SAS) AF: 0.00319 AC: 15 AN: 4708

European-Finnish (FIN) AF: 0.00171 AC: 18 AN: 10504

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.000548 AC: 37 AN: 67520

Other (OTH) AF: 0.000959 AC: 2 AN: 2086

Alfa AF: 0.000849 Hom.: 0

Bravo AF: 0.000635

ESP6500AA AF: 0.000242 AC: 1

ESP6500EA AF: 0.000242 AC: 2

ExAC AF: 0.000895 AC: 99

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not provided (5)
-	-	1	Autosomal dominant polycystic kidney disease (1)
-	-	1	not specified (1)
-	-	1	Polycystic kidney disease (1)
-	-	1	Polycystic kidney disease, adult type (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	14
DANN	Benign	0.95
DEOGEN2	Benign	0.23	T
Eigen	Benign	-0.92
Eigen_PC	Benign	-0.97
FATHMM_MKL	Benign	0.53	D
LIST_S2	Benign	0.80	T
M_CAP	Pathogenic	0.37	D
MetaRNN	Benign	0.0088	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.0	L
PhyloP100		4.1
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.12
Sift	Benign	0.081	T
Sift4G	Benign	0.088	T
Polyphen		0.60	P
Vest4		0.056
MVP		0.49
ClinPred		0.020	T
GERP RS		-0.39
Varity_R		0.027
gMVP		0.15
Mutation Taster		=77/23	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: rs200509641; hg19: chr16-2154549; COSMIC: COSV51913852; COSMIC: COSV51913852;