rs9926309

Variant names:

• chr16-2102849-A-G
• rs9926309
• NM_001009944.3:c.8913T>C

Your query was ambiguous. Multiple possible variants found:

• chr16-2102849-A-G
• chr16-2102849-A-C

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_001009944.3(PKD1):​c.8913T>C​(p.Ala2971Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00547 in 1,594,920 control chromosomes in the GnomAD database, including 450 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.032 (241 hom., cov: 32)
  • Exomes 𝑓: 0.0029 (209 hom.)
• Consequence: PKD1 NM_001009944.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -1.96
• Publications: 3 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.036).
• BP6: Variant 16-2102849-A-G is Benign according to our data. Variant chr16-2102849-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 257031.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.96 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.108 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.8913T>C	p.Ala2971Ala	synonymous	Exon 24 of 46	NP_001009944.3	P98161-1
	PKD1	NM_000296.4		c.8913T>C	p.Ala2971Ala	synonymous	Exon 24 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.8913T>C	p.Ala2971Ala	synonymous	Exon 24 of 46	ENSP00000262304.4	P98161-1
	PKD1	ENST00000423118.5	TSL:1	c.8913T>C	p.Ala2971Ala	synonymous	Exon 24 of 46	ENSP00000399501.1	P98161-3
	PKD1	ENST00000480227.5	TSL:1	n.650T>C		non_coding_transcript_exon	Exon 2 of 8

Frequencies

GnomAD3 genomes AF: 0.0319 AC: 4444 AN: 139172 Hom.: 242 Cov.: 32

Gnomad AFR AF: 0.111

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0111

Gnomad ASJ AF: 0.000932

Gnomad EAS AF: 0.00107

Gnomad SAS AF: 0.000236

Gnomad FIN AF: 0.000101

Gnomad MID AF: 0.00680

Gnomad NFE AF: 0.000812

Gnomad OTH AF: 0.0299

GnomAD2 exomes AF: 0.00775 AC: 1928 AN: 248664 AF XY: 0.00559

Gnomad AFR exome AF: 0.102

Gnomad AMR exome AF: 0.00660

Gnomad ASJ exome AF: 0.000902

Gnomad EAS exome AF: 0.000163

Gnomad FIN exome AF: 0.0000472

Gnomad NFE exome AF: 0.000420

Gnomad OTH exome AF: 0.00279

GnomAD4 exome AF: 0.00293 AC: 4262 AN: 1455626 Hom.: 209 Cov.: 34 AF XY: 0.00248 AC XY: 1798 AN XY: 724176

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

African (AFR) AF: 0.0964 AC: 3147 AN: 32630

American (AMR) AF: 0.00738 AC: 328 AN: 44456

Ashkenazi Jewish (ASJ) AF: 0.000804 AC: 21 AN: 26114

East Asian (EAS) AF: 0.000227 AC: 9 AN: 39674

South Asian (SAS) AF: 0.000244 AC: 21 AN: 86010

European-Finnish (FIN) AF: 0.0000387 AC: 2 AN: 51724

Middle Eastern (MID) AF: 0.00484 AC: 20 AN: 4134

European-Non Finnish (NFE) AF: 0.000260 AC: 289 AN: 1110828

Other (OTH) AF: 0.00708 AC: 425 AN: 60056

⚠️ 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: 0.0320 AC: 4458 AN: 139294 Hom.: 241 Cov.: 32 AF XY: 0.0308 AC XY: 2089 AN XY: 67908

African (AFR) AF: 0.111 AC: 4187 AN: 37680

American (AMR) AF: 0.0111 AC: 153 AN: 13802

Ashkenazi Jewish (ASJ) AF: 0.000932 AC: 3 AN: 3220

East Asian (EAS) AF: 0.00108 AC: 5 AN: 4648

South Asian (SAS) AF: 0.000237 AC: 1 AN: 4226

European-Finnish (FIN) AF: 0.000101 AC: 1 AN: 9930

Middle Eastern (MID) AF: 0.00730 AC: 2 AN: 274

European-Non Finnish (NFE) AF: 0.000812 AC: 51 AN: 62798

Other (OTH) AF: 0.0294 AC: 55 AN: 1868

Alfa AF: 0.00818 Hom.: 15

Bravo AF: 0.0336

EpiCase AF: 0.000654

EpiControl AF: 0.000593

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	3	not provided (3)
-	-	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	-0.93
CADD	Benign	0.071
DANN	Benign	0.41
PhyloP100		-2.0
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: rs9926309; hg19: chr16-2152850;