NM_001009944.3:c.288-11G>C

Variant names:

• chr16-2119196-C-G
• rs750270591
• NM_001009944.3:c.288-11G>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BP6_Very_Strong

The NM_001009944.3(PKD1):​c.288-11G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000036 (11 hom.)
  • Failed GnomAD Quality Control
• Consequence: PKD1 NM_001009944.3 intron
• Scores: Splicing: ADA: 0.000009816
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.923
• Publications: 0 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: ClinGen, Orphanet
• 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

ENSG00000260447 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.96).
• BP6: Variant 16-2119196-C-G is Benign according to our data. Variant chr16-2119196-C-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 433941.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PKD1	NM_001009944.3	c.288-11G>C		intron_variant	Intron 2 of 45	ENST00000262304.9	NP_001009944.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PKD1	ENST00000262304.9	c.288-11G>C		intron_variant	Intron 2 of 45	1	NM_001009944.3	ENSP00000262304.4
PKD1	ENST00000423118.5	c.288-11G>C		intron_variant	Intron 2 of 45	1		ENSP00000399501.1
ENSG00000260447	ENST00000562027.1	n.-11C>G		upstream_gene_variant		5

Frequencies

GnomAD3 genomes AF: 0.000132 AC: 20 AN: 151912 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00258

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000480 AC: 107 AN: 223052 AF XY: 0.000430

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000592

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00614

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000974

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000362 AC: 51 AN: 1407896 Hom.: 11 Cov.: 24 AF XY: 0.0000398 AC XY: 28 AN XY: 702840

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000307 AC: 1 AN: 32556

American (AMR) AF: 0.00 AC: 0 AN: 44482

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25932

East Asian (EAS) AF: 0.00104 AC: 40 AN: 38526

South Asian (SAS) AF: 0.00 AC: 0 AN: 85086

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 37868

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4076

European-Non Finnish (NFE) AF: 0.00000370 AC: 4 AN: 1080550

Other (OTH) AF: 0.000102 AC: 6 AN: 58820

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.000132 AC: 20 AN: 152018 Hom.: 0 Cov.: 32 AF XY: 0.000135 AC XY: 10 AN XY: 74304

African (AFR) AF: 0.000121 AC: 5 AN: 41442

American (AMR) AF: 0.0000654 AC: 1 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00259 AC: 13 AN: 5026

South Asian (SAS) AF: 0.00 AC: 0 AN: 4810

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68030

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.000130 Hom.: 0

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

May 08, 2019

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 01, 2021

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 22185115) -

Polycystic kidney disease, adult type Benign:1

Feb 03, 2020

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Polycystic kidney disease Benign:1

-

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

The PKD1 c.288-11G>C variant was identified in a ADPKD mutational analysis study of PKD1 and PKD2 genes in Chinese individuals or families with ADPKD, and was present in 4 of 200 control chromosomes (frequency: 0.020) from healthy individuals (Yu 2011). The variant was identified in the ADPKD Mutation Database (classification likely neutral), but was not identified in dbSNP, 1000 Genomes, NHLBI GO Exome Sequencing Project, the Exome Aggregation Consortium (March 2016), Clinvitae, ClinVar, GeneInsight COGR, PKD1-LOVD, and PKD1-LOVD 3.0 databases. The variant occurs outside of the splicing consensus sequence and 1 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	0.32
DANN	Benign	0.42
PhyloP100		-0.92
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0000098
dbscSNV1_RF	Benign	0.0
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: rs750270591; hg19: chr16-2169197;