rs746333408

Positions:

• chr16-2103306-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Very_Strong BP7 BS2_Supporting

The NM_001009944.3(PKD1):​c.8751G>A​(p.Ala2917=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00014 in 1,608,752 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00014 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00014 (0 hom.)
• Consequence: PKD1 NM_001009944.3 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.945

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.64).
• BP6: Variant 16-2103306-C-T is Benign according to our data. Variant chr16-2103306-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 257029.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2103306-C-T is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-0.945 with no splicing effect.
• BS2: High AC in GnomAd4 at 22 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PKD1	NM_001009944.3	c.8751G>A	p.Ala2917=	synonymous_variant	23/46	ENST00000262304.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PKD1	ENST00000262304.9	c.8751G>A	p.Ala2917=	synonymous_variant	23/46	1	NM_001009944.3	P5

Frequencies

GnomAD3 genomes AF: 0.000145 AC: 22 AN: 152210 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000289

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000827 AC: 20 AN: 241894 Hom.: 0 AF XY: 0.0000827 AC XY: 11 AN XY: 133026

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000291

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000557

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000147

Gnomad OTH exome AF: 0.000168

GnomAD4 exome AF: 0.000139 AC: 203 AN: 1456542 Hom.: 0 Cov.: 34 AF XY: 0.000117 AC XY: 85 AN XY: 724716

Gnomad4 AFR exome AF: 0.0000599

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000165

Gnomad4 OTH exome AF: 0.000166

GnomAD4 genome AF: 0.000145 AC: 22 AN: 152210 Hom.: 0 Cov.: 32 AF XY: 0.000161 AC XY: 12 AN XY: 74364

Gnomad4 AFR AF: 0.000289

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000154 Hom.: 0

Bravo AF: 0.000162

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

Feb 01, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.64
CADD	Benign	5.1
DANN	Benign	0.72
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: rs746333408; hg19: chr16-2153307;