16-2119318-C-T

Variant names:

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_001009944.3(PKD1):c.276G>A(p.Ala92Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00312 in 1,288,016 control chromosomes in the GnomAD database, including 17 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0039 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0030 ( 16 hom. )

Consequence

PKD1
NM_001009944.3 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: -2.42

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:

ENSG00000260447 (HGNC:):

ENSG00000260447 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.85).

BP6

Variant 16-2119318-C-T is Benign according to our data. Variant chr16-2119318-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 433940.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2119318-C-T is described in Lovd as [Likely_benign].

BP7

Synonymous conserved (PhyloP=-2.42 with no splicing effect.

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00386 (587/152260) while in subpopulation SAS AF= 0.00974 (47/4824). AF 95% confidence interval is 0.00753. There are 1 homozygotes in gnomad4. There are 302 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 587 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PKD1	NM_001009944.3 link	c.276G>A	p.Ala92Ala	synonymous_variant	Exon 2 of 46	ENST00000262304.9	NP_001009944.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
PKD1	ENST00000262304.9 link	c.276G>A	p.Ala92Ala	synonymous_variant	Exon 2 of 46	1	NM_001009944.3	ENSP00000262304.4	P98161-1
PKD1	ENST00000423118.5 link	c.276G>A	p.Ala92Ala	synonymous_variant	Exon 2 of 46	1		ENSP00000399501.1	P98161-3
ENSG00000260447	ENST00000562027.1 link	n.112C>T		non_coding_transcript_exon_variant	Exon 1 of 2	5

Frequencies

GnomAD3 genomes

AF:

0.00385

AC:

586

AN:

152142

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000700

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00589

Gnomad ASJ

AF:

0.0161

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00973

Gnomad FIN

AF:

0.00320

Gnomad MID

AF:

0.0190

Gnomad NFE

AF:

0.00465

Gnomad OTH

AF:

0.00382

GnomAD3 exomes

AF:

0.00585

AC:

790

AN:

135112

Hom.:

AF XY:

0.00632

AC XY:

464

AN XY:

73432

show subpopulations

Gnomad AFR exome

AF:

0.000310

Gnomad AMR exome

AF:

0.00360

Gnomad ASJ exome

AF:

0.0125

Gnomad EAS exome

AF:

0.000190

Gnomad SAS exome

AF:

0.0114

Gnomad FIN exome

AF:

0.00431

Gnomad NFE exome

AF:

0.00538

Gnomad OTH exome

AF:

0.00654

GnomAD4 exome

AF:

0.00302

AC:

3432

AN:

1135756

Hom.:

Cov.:

AF XY:

0.00348

AC XY:

1988

AN XY:

571350

show subpopulations

Gnomad4 AFR exome

AF:

0.000410

Gnomad4 AMR exome

AF:

0.00333

Gnomad4 ASJ exome

AF:

0.0125

Gnomad4 EAS exome

AF:

0.0000867

Gnomad4 SAS exome

AF:

0.00901

Gnomad4 FIN exome

AF:

0.00373

Gnomad4 NFE exome

AF:

0.00231

Gnomad4 OTH exome

AF:

0.00412

GnomAD4 genome

AF:

0.00386

AC:

587

AN:

152260

Hom.:

Cov.:

AF XY:

0.00406

AC XY:

302

AN XY:

74432

show subpopulations

Gnomad4 AFR

AF:

0.000698

Gnomad4 AMR

AF:

0.00588

Gnomad4 ASJ

AF:

0.0161

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00974

Gnomad4 FIN

AF:

0.00320

Gnomad4 NFE

AF:

0.00466

Gnomad4 OTH

AF:

0.00378

Alfa

AF:

0.00374

Hom.:

Bravo

AF:

0.00371

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Oct 09, 2017

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jan 15, 2020

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 11857740, 11840199, 11316854, 22383692, 11115377) -

Dec 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PKD1: BP4, BP7, BS2 -

Polycystic kidney disease, adult type

Benign:2

Apr 06, 2020

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 29, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified

Benign:1

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

The PKD1 p.Ala92Ala variant was identified in 3 of 722 proband chromosomes (frequency: 0.004) from individuals or families with ADPKD (Rossetti 2001, Rossetti 2012). The variant was also identified in dbSNP (ID: rs374518168) as â€šÃ„ÃºNAâ€šÃ„Ã¹ and in the 1000 Genomes Project in 20 of 5000 chromosomes (frequency: 0.004). The variant was also identified in the Exome Aggregation Consortium database (March 14, 2016) in 126 of 12248 chromosomes (frequency: 0.010) specifically in 3 in 188 (frequency: 0.016) Latino alleles, 90 in 7570 (frequency: 0.012) South Asians alleles including 3 homozygous individuals, 30 in 3556 (frequency: 0.008) European Non Finnish alleles, 1 in 578 (frequency: 0.002) African alleles, 2 in 134 (frequency: 0.015) other alleles, increasing the likelihood this could be a low frequency benign variant. In addition, the variant was listed in the GeneInsight COGR (1x benign) and in the ADPKD Mutation database (6x â€šÃ„ÃºLikely Neutralâ€šÃ„Ã¹). The p.Ala92Ala variant is not expected to have clinical significance because it does not result in a change of amino acid and is not located in a known consensus splice site. In addition, in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information, this variant is classified as benign. -

Autosomal dominant polycystic kidney disease

Benign:1

Jan 01, 2019

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

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: research

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.85

CADD

Benign

1.8

DANN

Benign

0.71

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