rs377692278

Positions:

• chr16-2091608-G-A

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_001009944.3(PKD1):​c.11538-11C>T variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00181 in 1,560,680 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0014 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0019 (3 hom.)
• Consequence: PKD1 NM_001009944.3 splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00005669
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.153

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-AS1 (HGNC:56035): (PKD1 antisense RNA 1)

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 16-2091608-G-A is Benign according to our data. Variant chr16-2091608-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 256905.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2091608-G-A is described in Lovd as [Likely_benign].
• BS2: High AC in GnomAd4 at 206 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PKD1	NM_001009944.3	c.11538-11C>T		splice_polypyrimidine_tract_variant, intron_variant		ENST00000262304.9
PKD1-AS1	NR_135175.1	n.173G>A		non_coding_transcript_exon_variant	1/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PKD1	ENST00000262304.9	c.11538-11C>T		splice_polypyrimidine_tract_variant, intron_variant		1	NM_001009944.3	P5
PKD1-AS1	ENST00000563284.3	n.70G>A		splice_region_variant, non_coding_transcript_exon_variant	1/4	3

Frequencies

GnomAD3 genomes AF: 0.00135 AC: 206 AN: 152082 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000869

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00203

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.000283

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00194

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.00152 AC: 261 AN: 172118 Hom.: 0 AF XY: 0.00158 AC XY: 151 AN XY: 95820

Gnomad AFR exome AF: 0.000511

Gnomad AMR exome AF: 0.000884

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000696

Gnomad SAS exome AF: 0.000367

Gnomad FIN exome AF: 0.000981

Gnomad NFE exome AF: 0.00273

Gnomad OTH exome AF: 0.00172

GnomAD4 exome AF: 0.00186 AC: 2617 AN: 1408480 Hom.: 3 Cov.: 32 AF XY: 0.00182 AC XY: 1267 AN XY: 697176

Gnomad4 AFR exome AF: 0.000368

Gnomad4 AMR exome AF: 0.000809

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000527

Gnomad4 SAS exome AF: 0.000690

Gnomad4 FIN exome AF: 0.00108

Gnomad4 NFE exome AF: 0.00219

Gnomad4 OTH exome AF: 0.00140

GnomAD4 genome AF: 0.00135 AC: 206 AN: 152200 Hom.: 1 Cov.: 33 AF XY: 0.00128 AC XY: 95 AN XY: 74426

Gnomad4 AFR AF: 0.000866

Gnomad4 AMR AF: 0.00203

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.000283

Gnomad4 NFE AF: 0.00194

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.00146 Hom.: 0

Bravo AF: 0.00140

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 25, 2023	- -

Polycystic kidney disease, adult type Benign:2

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jan 06, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Aug 03, 2021	- -

Polycystic kidney disease Benign:1

Likely benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The PKD1 c.11538-11C>T variant was identified in 5 of 916 proband chromosomes (frequency: 0.005) from French and North American individuals or families with ADPKD (Garcia-Gonzalez 2007, Perrichot 1999, Rossetti 2012). The variant was also identified in dbSNP (ID: rs377692278) “With Likely benign allele”, ClinVar (classified likely benign by Prevention Genetics), and ADPKD Mutation Database (as likely neutral), but was not identified in COGR, and PKD1-LOVD databases. The variant was identified in control databases in 286 of 199042 chromosomes at a frequency of 0.001 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Consortium Feb 27, 2017). Breakdown of the observations by population include African in 8 of 18176 chromosomes (freq: 0.0004), European Non-Finnish in 223 of 188344 chromosomes (freq: 0.003), South Asian in 9 of 24676 chromosomes (freq: 0.0004), Other in 8 of 5104 chromosomes (freq: 0.002), Latino in 26 of 28456 chromosomes (freq: 0.0009), East Asian in 1 of 15360 chromosomes (freq: 0.00007), and European Finnish in 11 of 10842 chromosomes (freq: 0.001); it was not observed in the Ashkenazi Jewish population. The variant occurs outside of the splicing consensus sequence and 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 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

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Apr 19, 2021

This variant is associated with the following publications: (PMID: 10987650, 22383692, 17574468) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	8.0
DANN	Benign	0.77
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000057
dbscSNV1_RF	Benign	0.0040
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

Other links and lift over

dbSNP: rs377692278; hg19: chr16-2141609;