rs144634185

Variant names:

• chr16-2109485-G-A
• rs144634185
• NM_001009944.3:c.5682C>T

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.5682C>T​(p.Ala1894Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00659 in 1,609,434 control chromosomes in the GnomAD database, including 40 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0050 (4 hom., cov: 33)
  • Exomes 𝑓: 0.0068 (36 hom.)
• Consequence: PKD1 NM_001009944.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 0.171
• 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 (BayesDel_noAF=-0.53).
• BP6: Variant 16-2109485-G-A is Benign according to our data. Variant chr16-2109485-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 256980.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.171 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00499 (761/152354) while in subpopulation NFE AF = 0.00851 (579/68024). AF 95% confidence interval is 0.00794. There are 4 homozygotes in GnomAd4. There are 357 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 4 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.5682C>T	p.Ala1894Ala	synonymous	Exon 15 of 46	NP_001009944.3	P98161-1
	PKD1	NM_000296.4		c.5682C>T	p.Ala1894Ala	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.5682C>T	p.Ala1894Ala	synonymous	Exon 15 of 46	ENSP00000262304.4	P98161-1
	PKD1	ENST00000423118.5	TSL:1	c.5682C>T	p.Ala1894Ala	synonymous	Exon 15 of 46	ENSP00000399501.1	P98161-3
	PKD1	ENST00000488185.2	TSL:5	c.471-1127C>T		intron	N/A	ENSP00000456672.1	H3BSE9

Frequencies

GnomAD3 genomes AF: 0.00501 AC: 762 AN: 152236 Hom.: 4 Cov.: 33

Gnomad AFR AF: 0.00164

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00464

Gnomad ASJ AF: 0.000865

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00165

Gnomad FIN AF: 0.00132

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00853

Gnomad OTH AF: 0.00812

GnomAD2 exomes AF: 0.00443 AC: 1069 AN: 241270 AF XY: 0.00451

Gnomad AFR exome AF: 0.00154

Gnomad AMR exome AF: 0.00400

Gnomad ASJ exome AF: 0.00143

Gnomad EAS exome AF: 0.0000555

Gnomad FIN exome AF: 0.00183

Gnomad NFE exome AF: 0.00719

Gnomad OTH exome AF: 0.00657

GnomAD4 exome AF: 0.00676 AC: 9851 AN: 1457080 Hom.: 36 Cov.: 35 AF XY: 0.00654 AC XY: 4743 AN XY: 724834

African (AFR) AF: 0.000988 AC: 33 AN: 33400

American (AMR) AF: 0.00408 AC: 182 AN: 44618

Ashkenazi Jewish (ASJ) AF: 0.00203 AC: 53 AN: 26082

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39640

South Asian (SAS) AF: 0.00120 AC: 103 AN: 86004

European-Finnish (FIN) AF: 0.00197 AC: 101 AN: 51364

Middle Eastern (MID) AF: 0.000219 AC: 1 AN: 4558

European-Non Finnish (NFE) AF: 0.00813 AC: 9032 AN: 1111300

Other (OTH) AF: 0.00574 AC: 345 AN: 60114

GnomAD4 genome AF: 0.00499 AC: 761 AN: 152354 Hom.: 4 Cov.: 33 AF XY: 0.00479 AC XY: 357 AN XY: 74496

African (AFR) AF: 0.00163 AC: 68 AN: 41598

American (AMR) AF: 0.00464 AC: 71 AN: 15312

Ashkenazi Jewish (ASJ) AF: 0.000865 AC: 3 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00166 AC: 8 AN: 4830

European-Finnish (FIN) AF: 0.00132 AC: 14 AN: 10620

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00851 AC: 579 AN: 68024

Other (OTH) AF: 0.00803 AC: 17 AN: 2116

Alfa AF: 0.00662 Hom.: 3

Bravo AF: 0.00512

EpiCase AF: 0.00698

EpiControl AF: 0.00803

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	3	not specified (3)
-	-	2	Polycystic kidney disease, adult type (2)
-	-	1	PKD1-related disorder (1)
-	-	1	Polycystic kidney disease (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.53
CADD	Benign	7.7
DANN	Benign	0.83
PhyloP100		0.17
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Mutation Taster		=100/0	polymorphism

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: rs144634185; hg19: chr16-2159486; COSMIC: COSV99239493; COSMIC: COSV99239493;