16-2090971-G-C

Position:

• chr16-2090971-G-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.11916C>G​(p.Arg3972=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000702 in 1,543,088 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 (★★). Synonymous variant affecting the same amino acid position (i.e. R3972R) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.0035 (1 hom., cov: 34)
  • Exomes 𝑓: 0.00039 (3 hom.)
• Consequence: PKD1 NM_001009944.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.650

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=-0.84).
• BP6: Variant 16-2090971-G-C is Benign according to our data. Variant chr16-2090971-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 811148.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2090971-G-C is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=0.65 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00351 (534/152200) while in subpopulation AFR AF= 0.0123 (512/41528). AF 95% confidence interval is 0.0114. There are 1 homozygotes in gnomad4. There are 249 alleles in male gnomad4 subpopulation. Median coverage is 34. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 534 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PKD1	NM_001009944.3	c.11916C>G	p.Arg3972=	synonymous_variant	43/46	ENST00000262304.9	NP_001009944.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PKD1	ENST00000262304.9	c.11916C>G	p.Arg3972=	synonymous_variant	43/46	1	NM_001009944.3	ENSP00000262304	P5

Frequencies

GnomAD3 genomes AF: 0.00352 AC: 535 AN: 152082 Hom.: 1 Cov.: 34

Gnomad AFR AF: 0.0124

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000917

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.000681 AC: 94 AN: 138110 Hom.: 0 AF XY: 0.000526 AC XY: 40 AN XY: 76056

Gnomad AFR exome AF: 0.0109

Gnomad AMR exome AF: 0.000481

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000424

Gnomad FIN exome AF: 0.000172

Gnomad NFE exome AF: 0.0000562

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000395 AC: 549 AN: 1390888 Hom.: 3 Cov.: 34 AF XY: 0.000342 AC XY: 235 AN XY: 687370

Gnomad4 AFR exome AF: 0.0125

Gnomad4 AMR exome AF: 0.000578

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000248

Gnomad4 FIN exome AF: 0.000117

Gnomad4 NFE exome AF: 0.0000600

Gnomad4 OTH exome AF: 0.000981

GnomAD4 genome AF: 0.00351 AC: 534 AN: 152200 Hom.: 1 Cov.: 34 AF XY: 0.00335 AC XY: 249 AN XY: 74412

Gnomad4 AFR AF: 0.0123

Gnomad4 AMR AF: 0.000916

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000736

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.0000949 Hom.: 12

Bravo AF: 0.00416

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Polycystic kidney disease, adult type Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Jul 17, 2021	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 01, 2018	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2022	PKD1: BS1, BS2 -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Polycystic kidney disease Benign:1

Benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The PKD1 p.Arg3972= variant was identified in 11 of 460 proband chromosomes (frequency: 0.0239) from individuals or families with PKD, and the study classified the variant as a polymorphism (Rossetti 2012). The variant was also identified in dbSNP (ID: rs77634115) as “With Benign allele”, ClinVar (1x as benign by Prevention Genetics), Clinvitae (as benign), ADPKD Mutation Database (as likely neutral). In addition, a different nucleotide change, c.11916C>T, with the same protein consequence, has been classified as benign in several databases, including ClinVar and Clinvitae. The variant was not identified in LOVD 3.0, and PKD1-LOVD databases. The variant was identified in control databases in 200 of 164424 chromosomes at a frequency of 0.0012, in the following populations: African in 181 (1 homozygous) of 15410 chromosomes (freq: 0.012), Latino in 12 of 25050 chromosomes (freq. 0.0005), Other in 1 of 4606 chromosomes (freq. 0.0002), European (Finnish) in 4 of 66128 (freq. 0.0001), European (Non-Finnish) in 4 of 66128 chromosomes (freq. 0.00006), and South Asian in 1 of 23662 chromosomes (freq. 0.00004), increasing the likelihood that this may be a low frequency benign variant in certain populations of origin (Genome Aggregation Consortium Feb 27, 2017). The p.Arg3972= 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 this variant meets our laboratory criteria to be classified as benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	4.6
DANN	Benign	0.59

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: rs77634115; hg19: chr16-2140972;