16-2111567-C-T

Position:

• chr16-2111567-C-T

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2_Supporting

The NM_001009944.3(PKD1):​c.3600G>A​(p.Ala1200Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000334 in 1,579,516 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 Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00025 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00034 (2 hom.)
• Consequence: PKD1 NM_001009944.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -1.08

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 -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.63).
• BP6: Variant 16-2111567-C-T is Benign according to our data. Variant chr16-2111567-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 586269.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2111567-C-T is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-1.08 with no splicing effect.
• BS1: Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.000343 (489/1427198) while in subpopulation MID AF= 0.0031 (14/4510). AF 95% confidence interval is 0.00188. There are 2 homozygotes in gnomad4_exome. There are 289 alleles in male gnomad4_exome subpopulation. Median coverage is 36. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 38 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	Protein	UniProt
PKD1	NM_001009944.3	c.3600G>A	p.Ala1200Ala	synonymous_variant	15/46	ENST00000262304.9	NP_001009944.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PKD1	ENST00000262304.9	c.3600G>A	p.Ala1200Ala	synonymous_variant	15/46	1	NM_001009944.3	ENSP00000262304.4

Frequencies

GnomAD3 genomes AF: 0.000256 AC: 39 AN: 152200 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000393

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000323

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000535 AC: 99 AN: 185190 Hom.: 0 AF XY: 0.000654 AC XY: 66 AN XY: 100894

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000392

Gnomad ASJ exome AF: 0.000906

Gnomad EAS exome AF: 0.0000724

Gnomad SAS exome AF: 0.00186

Gnomad FIN exome AF: 0.0000599

Gnomad NFE exome AF: 0.000352

Gnomad OTH exome AF: 0.000611

GnomAD4 exome AF: 0.000343 AC: 489 AN: 1427198 Hom.: 2 Cov.: 36 AF XY: 0.000408 AC XY: 289 AN XY: 707538

Gnomad4 AFR exome AF: 0.000153

Gnomad4 AMR exome AF: 0.000226

Gnomad4 ASJ exome AF: 0.000863

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00188

Gnomad4 FIN exome AF: 0.0000404

Gnomad4 NFE exome AF: 0.000230

Gnomad4 OTH exome AF: 0.000509

GnomAD4 genome AF: 0.000249 AC: 38 AN: 152318 Hom.: 0 Cov.: 33 AF XY: 0.000269 AC XY: 20 AN XY: 74482

Gnomad4 AFR AF: 0.0000481

Gnomad4 AMR AF: 0.000392

Gnomad4 ASJ AF: 0.00115

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000621

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000323

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000360 Hom.: 0

Bravo AF: 0.000242

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Dec 28, 2017	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2023	PKD1: BP4, BP7 -

Polycystic kidney disease, adult type Benign:1

Benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Jul 09, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.63
CADD	Benign	3.3
DANN	Benign	0.68

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs372882189; hg19: chr16-2161568;