chr16-2109995-G-A

Variant names:

• chr16-2109995-G-A
• rs9935526
• NM_001009944.3:c.5172C>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.5172C>T​(p.Ala1724Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.173 in 1,609,216 control chromosomes in the GnomAD database, including 29,040 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.25 (6284 hom., cov: 33)
  • Exomes 𝑓: 0.17 (22756 hom.)
• Consequence: PKD1 NM_001009944.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.914
• Publications: 17 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 16-2109995-G-A is Benign according to our data. Variant chr16-2109995-G-A is described in ClinVar as Benign. ClinVar VariationId is 256974.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.914 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.466 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.5172C>T	p.Ala1724Ala	synonymous	Exon 15 of 46	NP_001009944.3	P98161-1
	PKD1	NM_000296.4		c.5172C>T	p.Ala1724Ala	synonymous	Exon 15 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.5172C>T	p.Ala1724Ala	synonymous	Exon 15 of 46	ENSP00000262304.4	P98161-1
	PKD1	ENST00000423118.5	TSL:1	c.5172C>T	p.Ala1724Ala	synonymous	Exon 15 of 46	ENSP00000399501.1	P98161-3
	PKD1	ENST00000488185.2	TSL:5	c.471-1637C>T		intron	N/A	ENSP00000456672.1	H3BSE9

Frequencies

GnomAD3 genomes AF: 0.246 AC: 37417 AN: 152074 Hom.: 6269 Cov.: 33

Gnomad AFR AF: 0.471

Gnomad AMI AF: 0.134

Gnomad AMR AF: 0.181

Gnomad ASJ AF: 0.235

Gnomad EAS AF: 0.00135

Gnomad SAS AF: 0.0867

Gnomad FIN AF: 0.191

Gnomad MID AF: 0.234

Gnomad NFE AF: 0.164

Gnomad OTH AF: 0.241

GnomAD2 exomes AF: 0.161 AC: 38922 AN: 242448 AF XY: 0.155

Gnomad AFR exome AF: 0.486

Gnomad AMR exome AF: 0.109

Gnomad ASJ exome AF: 0.232

Gnomad EAS exome AF: 0.000167

Gnomad FIN exome AF: 0.185

Gnomad NFE exome AF: 0.166

Gnomad OTH exome AF: 0.177

GnomAD4 exome AF: 0.165 AC: 240747 AN: 1457024 Hom.: 22756 Cov.: 35 AF XY: 0.163 AC XY: 117821 AN XY: 724784

African (AFR) AF: 0.484 AC: 16149 AN: 33370

American (AMR) AF: 0.119 AC: 5300 AN: 44606

Ashkenazi Jewish (ASJ) AF: 0.238 AC: 6206 AN: 26102

East Asian (EAS) AF: 0.000277 AC: 11 AN: 39672

South Asian (SAS) AF: 0.0896 AC: 7713 AN: 86070

European-Finnish (FIN) AF: 0.183 AC: 9484 AN: 51912

Middle Eastern (MID) AF: 0.231 AC: 977 AN: 4226

European-Non Finnish (NFE) AF: 0.166 AC: 184248 AN: 1110988

Other (OTH) AF: 0.177 AC: 10659 AN: 60078

GnomAD4 genome AF: 0.246 AC: 37477 AN: 152192 Hom.: 6284 Cov.: 33 AF XY: 0.241 AC XY: 17950 AN XY: 74402

African (AFR) AF: 0.471 AC: 19574 AN: 41520

American (AMR) AF: 0.181 AC: 2762 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.235 AC: 817 AN: 3470

East Asian (EAS) AF: 0.00135 AC: 7 AN: 5180

South Asian (SAS) AF: 0.0863 AC: 417 AN: 4830

European-Finnish (FIN) AF: 0.191 AC: 2025 AN: 10610

Middle Eastern (MID) AF: 0.235 AC: 69 AN: 294

European-Non Finnish (NFE) AF: 0.164 AC: 11181 AN: 67974

Other (OTH) AF: 0.238 AC: 503 AN: 2112

Alfa AF: 0.196 Hom.: 1162

Bravo AF: 0.257

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.10
DANN	Benign	0.74
PhyloP100		-0.91
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: rs9935526; hg19: chr16-2159996; COSMIC: COSV51920023; COSMIC: COSV51920023;