rs144817614

Variant names:

• chr16-2100209-C-T
• rs144817614
• NM_001009944.3:c.9669G>A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001009944.3(PKD1):​c.9669G>A​(p.Thr3223Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00425 in 1,610,124 control chromosomes in the GnomAD database, including 99 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.015 (43 hom., cov: 32)
  • Exomes 𝑓: 0.0031 (56 hom.)
• Consequence: PKD1 NM_001009944.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -4.42

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]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.62).
• BP6: Variant 16-2100209-C-T is Benign according to our data. Variant chr16-2100209-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 257044.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2100209-C-T is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-4.42 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0149 (2272/152328) while in subpopulation AFR AF= 0.0389 (1617/41588). AF 95% confidence interval is 0.0373. There are 43 homozygotes in gnomad4. There are 1161 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 2272 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PKD1	NM_001009944.3	c.9669G>A	p.Thr3223Thr	synonymous_variant	Exon 28 of 46	ENST00000262304.9	NP_001009944.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PKD1	ENST00000262304.9	c.9669G>A	p.Thr3223Thr	synonymous_variant	Exon 28 of 46	1	NM_001009944.3	ENSP00000262304.4

Frequencies

GnomAD3 genomes AF: 0.0149 AC: 2267 AN: 152210 Hom.: 43 Cov.: 32

Gnomad AFR AF: 0.0389

Gnomad AMI AF: 0.0285

Gnomad AMR AF: 0.0251

Gnomad ASJ AF: 0.0173

Gnomad EAS AF: 0.000387

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0316

Gnomad NFE AF: 0.00197

Gnomad OTH AF: 0.0191

GnomAD3 exomes AF: 0.00580 AC: 1420 AN: 244826 Hom.: 16 AF XY: 0.00502 AC XY: 672 AN XY: 133826

Gnomad AFR exome AF: 0.0375

Gnomad AMR exome AF: 0.0102

Gnomad ASJ exome AF: 0.0191

Gnomad EAS exome AF: 0.000220

Gnomad SAS exome AF: 0.000164

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00245

Gnomad OTH exome AF: 0.00866

GnomAD4 exome AF: 0.00314 AC: 4572 AN: 1457796 Hom.: 56 Cov.: 32 AF XY: 0.00295 AC XY: 2136 AN XY: 725244

Gnomad4 AFR exome AF: 0.0390

Gnomad4 AMR exome AF: 0.0108

Gnomad4 ASJ exome AF: 0.0183

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.000151

Gnomad4 FIN exome AF: 0.0000576

Gnomad4 NFE exome AF: 0.00156

Gnomad4 OTH exome AF: 0.00763

GnomAD4 genome AF: 0.0149 AC: 2272 AN: 152328 Hom.: 43 Cov.: 32 AF XY: 0.0156 AC XY: 1161 AN XY: 74484

Gnomad4 AFR AF: 0.0389

Gnomad4 AMR AF: 0.0250

Gnomad4 ASJ AF: 0.0173

Gnomad4 EAS AF: 0.000387

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00197

Gnomad4 OTH AF: 0.0189

Alfa AF: 0.00783 Hom.: 6

Bravo AF: 0.0172

EpiCase AF: 0.00289

EpiControl AF: 0.00320

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jul 25, 2018

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 30, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 29860066, 22383692, 17574468, 11967008, 11115377, 10923040) -

Polycystic kidney disease, adult type Benign:2

Jul 23, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 21, 2019

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

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: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

The PKD1 p.Thr3223Thr variant was identified in 7 of 970 proband chromosomes (frequency: 0.007) from individuals or families with ADPKD (Rossetti 2001, Rossetti 2002, Rossetti 2012, Garcia-Gonzalez 2007). In all these studies, the variant was identified as a polymorphism, and in one study occurring in the homozygous state, frequency unspecified (Koptides 2000). The variant was identified in dbSNP (ID:rs144817614) as “NA”, ADPKD Mutation Database (as Likely Neutral), but not in the Clinvitae, ClinVar, GeneInsight COGR, MutDB, PKD1-LOVD, and PKD1-LOVD 3.0 databases. This variant was also identified in the 1000 Genomes Project in 79 of 5000 chromosomes (frequency: 0.0158), HAPMAP populations: EAS in 2 of 1008 chromosomes (frequency: 0.002)/EUR in 7 of 1006 chromosomes (frequency: 0.007), in NHLBI GO Exome Sequencing Project in 15 of 5384 European American alleles (frequency: 0.00279) and in 89 of 3000 African American alleles (frequency: 0.02967), and in the Exome Aggregation Consortium database (March 14, 2016) in 615 of 113462 chromosomes (freq. 0.00542) in the following populations: African in 328 (8 homozygous) of 8492 chromosomes (freq. 0.03862), Other in 9 of 852 chromosomes (freq. 0.01056), Latino in 83 of 11316 chromosomes (freq. 0.000734), European (Non-Finnish) in 192 of 61484 chromosomes (freq. 0.00312), Finnish in 1 of 6518 chromosomes (freq. 0.00015) and East Asian in 1 of 8362 chromosomes (freq. 0.0001) and South Asian in 1 of 16438 chromosomes (freq. 0.00006), however we cannot be certain that data from control databases is specific to PKD1 and not from one of the six PKD1 pseudogenes. The p.Thr3223Thr 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. 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, this variant is classified as benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.62
CADD	Benign	0.078
DANN	Benign	0.89

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs144817614; hg19: chr16-2150210;