rs972049140

Positions:

chr16-2135616-C-A

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_001009944.3(PKD1):c.74G>T(p.Gly25Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000586 in 981,904 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. GP25D?) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.00043 ( 0 hom., cov: 31)

Exomes 𝑓: 0.00061 ( 1 hom. )

Consequence

PKD1
NM_001009944.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:2

Conservation

PhyloP100: -1.77

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.032297462).

BP6

Variant 16-2135616-C-A is Benign according to our data. Variant chr16-2135616-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 448005.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1, Benign=1}.

BS2

High AC in GnomAd4 at 63 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
PKD1	NM_001009944.3 linkuse as main transcript	c.74G>T	p.Gly25Val	missense_variant	1/46	ENST00000262304.9	NP_001009944.3
PKD1	NM_000296.4 linkuse as main transcript	c.74G>T	p.Gly25Val	missense_variant	1/46		NP_000287.4
PKD1	XM_047434208.1 linkuse as main transcript	c.74G>T	p.Gly25Val	missense_variant	1/48		XP_047290164.1
PKD1	XM_047434209.1 linkuse as main transcript	c.74G>T	p.Gly25Val	missense_variant	1/47		XP_047290165.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PKD1	ENST00000262304.9 linkuse as main transcript	c.74G>T	p.Gly25Val	missense_variant	1/46	1	NM_001009944.3	ENSP00000262304.4		P98161-1
PKD1	ENST00000423118.5 linkuse as main transcript	c.74G>T	p.Gly25Val	missense_variant	1/46	1		ENSP00000399501.1		P98161-3

Frequencies

GnomAD3 genomes

AF:

0.000437

AC:

AN:

146620

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000538

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000235

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000607

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.000613

AC:

512

AN:

835190

Hom.:

Cov.:

AF XY:

0.000652

AC XY:

253

AN XY:

388074

show subpopulations

Gnomad4 AFR exome

AF:

0.000509

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000643

Gnomad4 OTH exome

AF:

0.000537

GnomAD4 genome

AF:

0.000429

AC:

AN:

146714

Hom.:

Cov.:

AF XY:

0.000392

AC XY:

AN XY:

71414

show subpopulations

Gnomad4 AFR

AF:

0.000536

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000235

Gnomad4 NFE

AF:

0.000592

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000427

Hom.:

Bravo

AF:

0.000314

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Autosomal dominant polycystic kidney disease

Uncertain:1

Uncertain significance, criteria provided, single submitter

research

Molecular Genetics of Inherited Kidney Disorders Laboratory, Garvan Institute of Medical Research

Jan 01, 2019

- -

PKD1-related disorder

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 01, 2023

The PKD1 c.74G>T variant is predicted to result in the amino acid substitution p.Gly25Val. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.050% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/16-2185617-C-A). Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

Oct 18, 2019

- -

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Feb 20, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.075

BayesDel_addAF

Benign

-0.54

BayesDel_noAF

Benign

-0.70

CADD

Benign

7.3

DANN

Benign

0.67

DEOGEN2

Benign

0.16

T;.

Eigen

Benign

-2.0

Eigen_PC

Benign

-2.1

FATHMM_MKL

Benign

0.0054

LIST_S2

Benign

0.32

T;T

M_CAP

Benign

0.026

MetaRNN

Benign

0.032

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.0

N;N

PrimateAI

Pathogenic

0.80

PROVEAN

Benign

-0.67

N;N

REVEL

Benign

0.016

Sift

Benign

0.24

T;T

Sift4G

Benign

0.35

T;T

Polyphen

0.0

B;B

Vest4

0.11

MutPred

0.29

Gain of helix (P = 0.1736);Gain of helix (P = 0.1736);

MVP

0.15

ClinPred

0.076

GERP RS

-6.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.6

Varity_R

0.062

gMVP

0.28

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over