rs76184385

Variant names:

• chr16-2102618-C-T
• rs76184385
• NM_001009944.3:c.8964G>A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001009944.3(PKD1):​c.8964G>A​(p.Ala2988Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00776 in 1,611,016 control chromosomes in the GnomAD database, including 73 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0064 (8 hom., cov: 33)
  • Exomes 𝑓: 0.0079 (65 hom.)
• Consequence: PKD1 NM_001009944.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -0.761
• Publications: 4 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 (REVEL=0.016).
• BP6: Variant 16-2102618-C-T is Benign according to our data. Variant chr16-2102618-C-T is described in ClinVar as Benign. ClinVar VariationId is 257036.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.761 with no splicing effect.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00637 (970/152370) while in subpopulation EAS AF = 0.00926 (48/5186). AF 95% confidence interval is 0.00717. There are 8 homozygotes in GnomAd4. There are 534 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 8 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.8964G>A	p.Ala2988Ala	synonymous	Exon 25 of 46	NP_001009944.3	P98161-1
	PKD1	NM_000296.4		c.8964G>A	p.Ala2988Ala	synonymous	Exon 25 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.8964G>A	p.Ala2988Ala	synonymous	Exon 25 of 46	ENSP00000262304.4	P98161-1
	PKD1	ENST00000423118.5	TSL:1	c.8964G>A	p.Ala2988Ala	synonymous	Exon 25 of 46	ENSP00000399501.1	P98161-3
	PKD1	ENST00000480227.5	TSL:1	n.701G>A		non_coding_transcript_exon	Exon 3 of 8

Frequencies

GnomAD3 genomes AF: 0.00638 AC: 971 AN: 152254 Hom.: 8 Cov.: 33

Gnomad AFR AF: 0.00123

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00569

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00923

Gnomad SAS AF: 0.00600

Gnomad FIN AF: 0.0206

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00769

Gnomad OTH AF: 0.00622

GnomAD2 exomes AF: 0.00748 AC: 1848 AN: 247014 AF XY: 0.00738

Gnomad AFR exome AF: 0.000521

Gnomad AMR exome AF: 0.00892

Gnomad ASJ exome AF: 0.000100

Gnomad EAS exome AF: 0.00985

Gnomad FIN exome AF: 0.0183

Gnomad NFE exome AF: 0.00660

Gnomad OTH exome AF: 0.00798

GnomAD4 exome AF: 0.00791 AC: 11537 AN: 1458646 Hom.: 65 Cov.: 34 AF XY: 0.00780 AC XY: 5660 AN XY: 725648

African (AFR) AF: 0.00138 AC: 46 AN: 33418

American (AMR) AF: 0.00803 AC: 359 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.000268 AC: 7 AN: 26122

East Asian (EAS) AF: 0.0145 AC: 574 AN: 39696

South Asian (SAS) AF: 0.00549 AC: 473 AN: 86164

European-Finnish (FIN) AF: 0.0186 AC: 970 AN: 52072

Middle Eastern (MID) AF: 0.00244 AC: 11 AN: 4506

European-Non Finnish (NFE) AF: 0.00774 AC: 8610 AN: 1111754

Other (OTH) AF: 0.00809 AC: 487 AN: 60202

GnomAD4 genome AF: 0.00637 AC: 970 AN: 152370 Hom.: 8 Cov.: 33 AF XY: 0.00717 AC XY: 534 AN XY: 74508

African (AFR) AF: 0.00123 AC: 51 AN: 41598

American (AMR) AF: 0.00568 AC: 87 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3472

East Asian (EAS) AF: 0.00926 AC: 48 AN: 5186

South Asian (SAS) AF: 0.00580 AC: 28 AN: 4830

European-Finnish (FIN) AF: 0.0206 AC: 219 AN: 10628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00769 AC: 523 AN: 68028

Other (OTH) AF: 0.00616 AC: 13 AN: 2112

Alfa AF: 0.00607 Hom.: 1

Bravo AF: 0.00515

Asia WGS AF: 0.00837 AC: 29 AN: 3478

EpiCase AF: 0.00692

EpiControl AF: 0.00670

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not provided (6)
-	-	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
BayesDel_noAF	Benign	-0.75
CADD	Benign	2.9
DANN	Benign	0.43
PhyloP100		-0.76
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.16		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: rs76184385; hg19: chr16-2152619; COSMIC: COSV51925897; COSMIC: COSV51925897;