16-2109860-A-G

Variant names:

• chr16-2109860-A-G
• rs575064371
• NM_001009944.3:c.5307T>C

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.5307T>C​(p.His1769His) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000373 in 1,610,398 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0021 (3 hom., cov: 33)
  • Exomes 𝑓: 0.00019 (2 hom.)
• Consequence: PKD1 NM_001009944.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.665

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=-1.01).
• BP6: Variant 16-2109860-A-G is Benign according to our data. Variant chr16-2109860-A-G is described in ClinVar as [Benign]. Clinvar id is 256976.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2109860-A-G is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-0.665 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00213 (325/152266) while in subpopulation AFR AF= 0.0072 (299/41550). AF 95% confidence interval is 0.00653. There are 3 homozygotes in gnomad4. There are 156 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 325 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PKD1	NM_001009944.3	c.5307T>C	p.His1769His	synonymous_variant	Exon 15 of 46	ENST00000262304.9	NP_001009944.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PKD1	ENST00000262304.9	c.5307T>C	p.His1769His	synonymous_variant	Exon 15 of 46	1	NM_001009944.3	ENSP00000262304.4

Frequencies

GnomAD3 genomes AF: 0.00214 AC: 325 AN: 152148 Hom.: 3 Cov.: 33

Gnomad AFR AF: 0.00722

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000786

Gnomad ASJ AF: 0.000864

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.000201 AC: 50 AN: 249144 Hom.: 0 AF XY: 0.000155 AC XY: 21 AN XY: 135346

Gnomad AFR exome AF: 0.00263

Gnomad AMR exome AF: 0.0000868

Gnomad ASJ exome AF: 0.000201

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000893

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.000189 AC: 275 AN: 1458132 Hom.: 2 Cov.: 34 AF XY: 0.000163 AC XY: 118 AN XY: 725356

Gnomad4 AFR exome AF: 0.00592

Gnomad4 AMR exome AF: 0.000291

Gnomad4 ASJ exome AF: 0.000574

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000171

Gnomad4 OTH exome AF: 0.000432

GnomAD4 genome AF: 0.00213 AC: 325 AN: 152266 Hom.: 3 Cov.: 33 AF XY: 0.00210 AC XY: 156 AN XY: 74456

Gnomad4 AFR AF: 0.00720

Gnomad4 AMR AF: 0.000785

Gnomad4 ASJ AF: 0.000864

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000882

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.000171 Hom.: 0

Bravo AF: 0.00254

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Feb 07, 2020

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Polycystic kidney disease, adult type Benign:1

Oct 01, 2018

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.His1769= variant was identified in 2 of 550 proband chromosomes (frequency: 0.003636) from individuals or families with autosomal dominant polycystic kidney disease (ADPKD) (Rossetti 2002, Rossetti 2012). The variant was also identified in dbSNP (ID: rs575064371) “With Benign allele,” ClinVar (as benign by Prevention Genetics), and ADPKD Mutation Database (2x as likely neutral). The variant was not identified in GeneInsight-COGR, LOVD 3.0, and PKD1-LOVD databases. The variant was identified in control databases in 105 of 275770 chromosomes at a frequency of 0.0004 increasing the likelihood that this may be a low frequency benign variant in certain populations of origin (Genome Aggregation Consortium Feb 27, 2017), being identified in the following populations: African in 98 of 23838 chromosomes (frequency: 0.004), Ashkenazi Jewish in 1of 10092 chromosomes (frequency: 0.0001), Latino in 3 of 34408 chromosomes (frequency: 0.00009), East Asian in 1 of 18858 chromosomes (frequency: 0.00005), and European Non-Finnish in 2 of 125618 chromosomes (frequency: 0.00002). In addition we cannot be certain that data from control databases is specific to PKD1 and not from one of the six PKD1 pseudogenes. The p.His1769= 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, 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.089
DANN	Benign	0.38
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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

Publications

LitVar

Other links and lift over

dbSNP: rs575064371; hg19: chr16-2159861; COSMIC: COSV99237541; COSMIC: COSV99237541;