rs11643513

Variant names:

• chr16-2117969-G-A
• rs11643513
• NM_001009944.3:c.1023C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001009944.3(PKD1):​c.1023C>T​(p.Ala341Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0432 in 1,538,560 control chromosomes in the GnomAD database, including 1,555 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.038 (178 hom., cov: 32)
  • Exomes 𝑓: 0.044 (1377 hom.)
• Consequence: PKD1 NM_001009944.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -1.11
• Publications: 6 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 16-2117969-G-A is Benign according to our data. Variant chr16-2117969-G-A is described in ClinVar as Benign. ClinVar VariationId is 256887.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.11 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0812 is higher than 0.05.

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.1023C>T	p.Ala341Ala	synonymous	Exon 5 of 46	NP_001009944.3	P98161-1
	PKD1	NM_000296.4		c.1023C>T	p.Ala341Ala	synonymous	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.1023C>T	p.Ala341Ala	synonymous	Exon 5 of 46	ENSP00000262304.4	P98161-1
	PKD1	ENST00000423118.5	TSL:1	c.1023C>T	p.Ala341Ala	synonymous	Exon 5 of 46	ENSP00000399501.1	P98161-3
	PKD1	ENST00000488185.2	TSL:5	c.108C>T	p.Ala36Ala	synonymous	Exon 1 of 5	ENSP00000456672.1	H3BSE9

Frequencies

GnomAD3 genomes AF: 0.0385 AC: 5860 AN: 152132 Hom.: 179 Cov.: 32

Gnomad AFR AF: 0.00898

Gnomad AMI AF: 0.0154

Gnomad AMR AF: 0.0852

Gnomad ASJ AF: 0.0242

Gnomad EAS AF: 0.000580

Gnomad SAS AF: 0.0128

Gnomad FIN AF: 0.0522

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.0498

Gnomad OTH AF: 0.0353

GnomAD2 exomes AF: 0.0493 AC: 6493 AN: 131760 AF XY: 0.0438

Gnomad AFR exome AF: 0.00891

Gnomad AMR exome AF: 0.124

Gnomad ASJ exome AF: 0.0247

Gnomad EAS exome AF: 0.000285

Gnomad FIN exome AF: 0.0577

Gnomad NFE exome AF: 0.0467

Gnomad OTH exome AF: 0.0477

GnomAD4 exome AF: 0.0437 AC: 60616 AN: 1386310 Hom.: 1377 Cov.: 28 AF XY: 0.0429 AC XY: 29595 AN XY: 690410

African (AFR) AF: 0.00682 AC: 219 AN: 32108

American (AMR) AF: 0.123 AC: 4987 AN: 40566

Ashkenazi Jewish (ASJ) AF: 0.0238 AC: 606 AN: 25478

East Asian (EAS) AF: 0.000237 AC: 9 AN: 38038

South Asian (SAS) AF: 0.0145 AC: 1198 AN: 82836

European-Finnish (FIN) AF: 0.0584 AC: 2167 AN: 37100

Middle Eastern (MID) AF: 0.0248 AC: 101 AN: 4066

European-Non Finnish (NFE) AF: 0.0461 AC: 49258 AN: 1068166

Other (OTH) AF: 0.0357 AC: 2071 AN: 57952

GnomAD4 genome AF: 0.0385 AC: 5860 AN: 152250 Hom.: 178 Cov.: 32 AF XY: 0.0389 AC XY: 2896 AN XY: 74430

African (AFR) AF: 0.00895 AC: 372 AN: 41564

American (AMR) AF: 0.0850 AC: 1301 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0242 AC: 84 AN: 3472

East Asian (EAS) AF: 0.000581 AC: 3 AN: 5164

South Asian (SAS) AF: 0.0130 AC: 63 AN: 4828

European-Finnish (FIN) AF: 0.0522 AC: 555 AN: 10624

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

European-Non Finnish (NFE) AF: 0.0499 AC: 3390 AN: 67980

Other (OTH) AF: 0.0350 AC: 74 AN: 2116

Alfa AF: 0.0453 Hom.: 29

Bravo AF: 0.0394

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	3	not specified (3)
-	-	2	Polycystic kidney disease, adult type (2)
-	-	1	Autosomal dominant polycystic kidney disease (1)
-	-	1	Polycystic kidney disease (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	1.2
DANN	Benign	0.73
PhyloP100		-1.1
PromoterAI		0.011	Neutral
Mutation Taster		=100/0	polymorphism (auto)

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: rs11643513; hg19: chr16-2167970; COSMIC: COSV51926039; COSMIC: COSV51926039;