rs377436997

Variant names:

• chr16-2091483-G-A
• rs377436997
• NM_001009944.3:c.11652C>T

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_Strong BP6_Moderate BP7 BS1

The NM_001009944.3(PKD1):​c.11652C>T​(p.Ser3884Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000141 in 1,378,046 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.00045 (1 hom., cov: 33)
  • Exomes 𝑓: 0.00010 (1 hom.)
• Consequence: PKD1 NM_001009944.3 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:2
• Conservation: PhyloP100: 0.0420
• 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 -11 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.64).
• BP6: Variant 16-2091483-G-A is Benign according to our data. Variant chr16-2091483-G-A is described in ClinVar as Benign. ClinVar VariationId is 434004.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=0.042 with no splicing effect.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000447 (67/149888) while in subpopulation EAS AF = 0.0123 (63/5128). AF 95% confidence interval is 0.00985. There are 1 homozygotes in GnomAd4. There are 36 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PKD1	NM_001009944.3	c.11652C>T	p.Ser3884Ser	synonymous_variant	Exon 42 of 46	ENST00000262304.9	NP_001009944.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PKD1	ENST00000262304.9	c.11652C>T	p.Ser3884Ser	synonymous_variant	Exon 42 of 46	1	NM_001009944.3	ENSP00000262304.4

Frequencies

GnomAD3 genomes AF: 0.000447 AC: 67 AN: 149780 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000665

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0122

Gnomad SAS AF: 0.000623

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000612 AC: 24 AN: 39214 AF XY: 0.000507

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0103

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000832

GnomAD4 exome AF: 0.000103 AC: 127 AN: 1228158 Hom.: 1 Cov.: 32 AF XY: 0.0000895 AC XY: 54 AN XY: 603220

African (AFR) AF: 0.00 AC: 0 AN: 22254

American (AMR) AF: 0.00 AC: 0 AN: 12756

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 17264

East Asian (EAS) AF: 0.00390 AC: 97 AN: 24898

South Asian (SAS) AF: 0.0000159 AC: 1 AN: 62704

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 30428

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3538

European-Non Finnish (NFE) AF: 0.00000995 AC: 10 AN: 1005232

Other (OTH) AF: 0.000387 AC: 19 AN: 49084

GnomAD4 genome AF: 0.000447 AC: 67 AN: 149888 Hom.: 1 Cov.: 33 AF XY: 0.000492 AC XY: 36 AN XY: 73182

African (AFR) AF: 0.00 AC: 0 AN: 41262

American (AMR) AF: 0.0000665 AC: 1 AN: 15048

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3448

East Asian (EAS) AF: 0.0123 AC: 63 AN: 5128

South Asian (SAS) AF: 0.000624 AC: 3 AN: 4808

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9732

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 290

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67184

Other (OTH) AF: 0.00 AC: 0 AN: 2076

Alfa AF: 0.000142 Hom.: 0

Bravo AF: 0.000423

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

Submissions by phenotype

Polycystic kidney disease, adult type Benign:1

Jan 07, 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 p.Ser3884= variant was not identified in the literature nor was it identified in the ClinVar, LOVD 3.0, or PKD1-LOVD databases. The variant was identified in dbSNP (ID: rs377436997) as “With Uncertain significance allele”, and ADPKD Mutation Database (classified likely neutral). The variant was identified in control databases in 52 (2 homozygous) of 67022 chromosomes at a frequency of 0.0008 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Other in 1 of 1998 chromosomes (freq: 0.0005), East Asian in 51 (2 homozygous) of 3682 chromosomes (freq: 0.01) while not observed in the African, Latino, European Non-Finnish, Ashkenazi Jewish, Finnish, and South Asian populations. The variant was also identified by our laboratory in 1 individual with polycystic kidneys. The p.Ser3884= 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.64
CADD	Benign	1.3
DANN	Benign	0.86
PhyloP100		0.042
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs377436997; hg19: chr16-2141484;