16-2135476-G-A

Position:

chr16-2135476-G-A

Variant summary

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

The NM_001009944.3(PKD1):c.214C>T(p.Leu72=) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000979 in 1,168,464 control chromosomes in the GnomAD database, including 17 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0046 ( 12 hom., cov: 31)

Exomes 𝑓: 0.00044 ( 5 hom. )

Consequence

PKD1
NM_001009944.3 splice_region, synonymous

Scores

Splicing: ADA: 0.0001990

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 2.31

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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.9).

BP6

Variant 16-2135476-G-A is Benign according to our data. Variant chr16-2135476-G-A is described in ClinVar as [Benign]. Clinvar id is 433938.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2135476-G-A is described in Lovd as [Likely_benign].

BP7

Synonymous conserved (PhyloP=2.31 with no splicing effect.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00461 (700/151706) while in subpopulation AFR AF= 0.0162 (672/41486). AF 95% confidence interval is 0.0152. There are 12 homozygotes in gnomad4. There are 321 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.

BS2

High AC in GnomAd4 at 700 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
PKD1	NM_001009944.3 linkuse as main transcript	c.214C>T	p.Leu72=	splice_region_variant, synonymous_variant	1/46	ENST00000262304.9
PKD1	NM_000296.4 linkuse as main transcript	c.214C>T	p.Leu72=	splice_region_variant, synonymous_variant	1/46
PKD1	XM_047434208.1 linkuse as main transcript	c.214C>T	p.Leu72=	splice_region_variant, synonymous_variant	1/48
PKD1	XM_047434209.1 linkuse as main transcript	c.214C>T	p.Leu72=	splice_region_variant, synonymous_variant	1/47

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PKD1	ENST00000262304.9 linkuse as main transcript	c.214C>T	p.Leu72=	splice_region_variant, synonymous_variant	1/46	1	NM_001009944.3	P5	P98161-1
PKD1	ENST00000423118.5 linkuse as main transcript	c.214C>T	p.Leu72=	splice_region_variant, synonymous_variant	1/46	1		A2	P98161-3

Frequencies

GnomAD3 genomes

AF:

0.00462

AC:

700

AN:

151598

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0162

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000985

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000443

Gnomad OTH

AF:

0.00480

GnomAD4 exome

AF:

0.000437

AC:

444

AN:

1016758

Hom.:

Cov.:

AF XY:

0.000399

AC XY:

191

AN XY:

478820

show subpopulations

Gnomad4 AFR exome

AF:

0.0195

Gnomad4 AMR exome

AF:

0.00154

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:

0.00000228

Gnomad4 OTH exome

AF:

0.000738

GnomAD4 genome

AF:

0.00461

AC:

700

AN:

151706

Hom.:

Cov.:

AF XY:

0.00433

AC XY:

321

AN XY:

74156

show subpopulations

Gnomad4 AFR

AF:

0.0162

Gnomad4 AMR

AF:

0.000983

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000443

Gnomad4 OTH

AF:

0.00475

Alfa

AF:

0.00520

Hom.:

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

Apr 27, 2017

- -

Polycystic kidney disease

Benign:1

Likely benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

The PKD1 p.Leu72= variant was identified in 2 of 164 proband chromosomes (frequency: 0.012) from individuals or families with ADPKD (Garcia-Gonzalez 2007). The variant was also found in in infant with ADPKD with co-occurring pathogenic variant PKD1 (c.8362_8363ins34) (Gilbert 2013), and in one individual in our laboratory with pathogenic mutation in PKD2 (c.1663C>T, p.Gln555*), increasing the likelihood that the p.Leu72= variant does not have clinical significance. The variant was also identified in dbSNP (ID: rs972113626) as "With other allele", ClinVar (classified as benign by Athena Diagnostics), and ADPKD Mutation Database (as likely neutral). The variant was identified in control databases in 132 of 29122 chromosomes at a frequency of 0.0045 (Genome Aggregation Database Feb 27, 2017), and observed in the following populations: African in 130 of 8606 chromosomes (freq: 0.015), European in 2 of 13928 chromosomes (freq. 0.00014), while not observed in the Other, Latino, Ashkenazi Jewish, East Asian, Finnish, and South Asian populations. The p.Leu72= 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) do not predict a difference in splicing. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign. -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Apr 01, 2020

This variant is associated with the following publications: (PMID: 23624871, 17574468) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.90

CADD

Benign

DANN

Benign

0.83

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00020

dbscSNV1_RF

Benign

0.080

SpliceAI score (max)

0.010

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