rs148164067

Variant names:

• chr16-2110621-C-T
• rs148164067
• NM_001009944.3:c.4546G>A
• PKD1 p.Ala1516Thr

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001009944.3(PKD1):​c.4546G>A​(p.Ala1516Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00673 in 1,610,296 control chromosomes in the GnomAD database, including 38 homozygotes. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0050 (2 hom., cov: 33)
  • Exomes 𝑓: 0.0069 (36 hom.)
• Consequence: PKD1 NM_001009944.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: -1.71
• Publications: 14 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, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.010074973).
• BP6: Variant 16-2110621-C-T is Benign according to our data. Variant chr16-2110621-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 256967.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00498 (758/152310) while in subpopulation NFE AF = 0.00766 (521/68018). AF 95% confidence interval is 0.00712. There are 2 homozygotes in GnomAd4. There are 363 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 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.4546G>A	p.Ala1516Thr	missense	Exon 15 of 46	NP_001009944.3	P98161-1
	PKD1	NM_000296.4		c.4546G>A	p.Ala1516Thr	missense	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.4546G>A	p.Ala1516Thr	missense	Exon 15 of 46	ENSP00000262304.4	P98161-1
	PKD1	ENST00000423118.5	TSL:1	c.4546G>A	p.Ala1516Thr	missense	Exon 15 of 46	ENSP00000399501.1	P98161-3
	PKD1	ENST00000488185.2	TSL:5	c.471-2263G>A		intron	N/A	ENSP00000456672.1	H3BSE9

Frequencies

GnomAD3 genomes AF: 0.00499 AC: 759 AN: 152192 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.00135

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000981

Gnomad ASJ AF: 0.0153

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00414

Gnomad FIN AF: 0.00828

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00766

Gnomad OTH AF: 0.00143

GnomAD2 exomes AF: 0.00576 AC: 1430 AN: 248178 AF XY: 0.00584

Gnomad AFR exome AF: 0.000818

Gnomad AMR exome AF: 0.000869

Gnomad ASJ exome AF: 0.0156

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00919

Gnomad NFE exome AF: 0.00775

Gnomad OTH exome AF: 0.00627

GnomAD4 exome AF: 0.00691 AC: 10077 AN: 1457986 Hom.: 36 Cov.: 36 AF XY: 0.00687 AC XY: 4981 AN XY: 725228

African (AFR) AF: 0.00102 AC: 34 AN: 33406

American (AMR) AF: 0.00116 AC: 52 AN: 44692

Ashkenazi Jewish (ASJ) AF: 0.0160 AC: 418 AN: 26106

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39690

South Asian (SAS) AF: 0.00447 AC: 385 AN: 86154

European-Finnish (FIN) AF: 0.00976 AC: 508 AN: 52038

Middle Eastern (MID) AF: 0.00797 AC: 34 AN: 4264

European-Non Finnish (NFE) AF: 0.00742 AC: 8251 AN: 1111460

Other (OTH) AF: 0.00655 AC: 394 AN: 60176

GnomAD4 genome AF: 0.00498 AC: 758 AN: 152310 Hom.: 2 Cov.: 33 AF XY: 0.00488 AC XY: 363 AN XY: 74458

African (AFR) AF: 0.00135 AC: 56 AN: 41566

American (AMR) AF: 0.000980 AC: 15 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.0153 AC: 53 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00414 AC: 20 AN: 4828

European-Finnish (FIN) AF: 0.00828 AC: 88 AN: 10624

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.00766 AC: 521 AN: 68018

Other (OTH) AF: 0.00142 AC: 3 AN: 2114

Alfa AF: 0.00730 Hom.: 2

Bravo AF: 0.00414

EpiCase AF: 0.00780

EpiControl AF: 0.00670

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not provided (5)
-	-	5	not specified (5)
-	-	1	PKD1-related disorder (1)
-	-	1	Polycystic kidney disease, adult type (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.63	T
BayesDel_noAF	Benign	-0.68
CADD	Benign	0.0030
DANN	Benign	0.81
DEOGEN2	Benign	0.14	T
Eigen	Benign	-2.0
Eigen_PC	Benign	-2.0
FATHMM_MKL	Benign	0.022	N
LIST_S2	Benign	0.29	T
M_CAP	Benign	0.066	D
MetaRNN	Benign	0.010	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.10	N
PhyloP100		-1.7
PrimateAI	Benign	0.32	T
PROVEAN	Benign	0.57	N
REVEL	Benign	0.017
Sift	Benign	0.51	T
Sift4G	Benign	0.51	T
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.021
gMVP		0.22
Mutation Taster		=90/10	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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs148164067;

hg19: chr16-2160622;