chr16-2091608-G-A

Variant names:

• chr16-2091608-G-A
• rs377692278
• NM_001009944.3:c.11538-11C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001009944.3(PKD1):​c.11538-11C>T variant causes a 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 intron
• Scores: Splicing: ADA: 0.00005669
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.153
• 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-AS1 (HGNC:56035): (PKD1 antisense RNA 1)

ACMG classification

Our verdict: Benign. The variant received -20 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.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00135 (206/152200) while in subpopulation AMR AF = 0.00203 (31/15302). AF 95% confidence interval is 0.00167. There are 1 homozygotes in GnomAd4. There are 95 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 3 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PKD1	NM_001009944.3	c.11538-11C>T		intron_variant	Intron 41 of 45	ENST00000262304.9	NP_001009944.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PKD1	ENST00000262304.9	c.11538-11C>T		intron_variant	Intron 41 of 45	1	NM_001009944.3	ENSP00000262304.4

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

GnomAD2 exomes AF: 0.00152 AC: 261 AN: 172118 AF XY: 0.00158

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 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

African (AFR) AF: 0.000368 AC: 12 AN: 32588

American (AMR) AF: 0.000809 AC: 32 AN: 39548

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24880

East Asian (EAS) AF: 0.0000527 AC: 2 AN: 37952

South Asian (SAS) AF: 0.000690 AC: 56 AN: 81188

European-Finnish (FIN) AF: 0.00108 AC: 38 AN: 35314

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4940

European-Non Finnish (NFE) AF: 0.00219 AC: 2395 AN: 1093462

Other (OTH) AF: 0.00140 AC: 82 AN: 58608

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

African (AFR) AF: 0.000866 AC: 36 AN: 41550

American (AMR) AF: 0.00203 AC: 31 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5172

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4830

European-Finnish (FIN) AF: 0.000283 AC: 3 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.00194 AC: 132 AN: 67948

Other (OTH) AF: 0.000473 AC: 1 AN: 2112

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

May 25, 2023

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Polycystic kidney disease, adult type Benign:2

Aug 03, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 06, 2019

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.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

Apr 19, 2021

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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
PhyloP100		0.15
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=96/4	polymorphism

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

Other links and lift over

dbSNP: rs377692278; hg19: chr16-2141609;