rs375283810

Positions:

• chr16-2104486-G-A
• chr16-2104486-G-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The ENST00000262304.9(PKD1):​c.8161+12C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000379 in 1,507,316 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0011 (2 hom., cov: 20)
  • Exomes 𝑓: 0.00030 (5 hom.)
• Consequence: PKD1 ENST00000262304.9 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.673

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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BP6: Variant 16-2104486-G-A is Benign according to our data. Variant chr16-2104486-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 257012.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2104486-G-A is described in Lovd as [Likely_benign].
• BS2: High AC in GnomAd4 at 166 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PKD1	NM_001009944.3	c.8161+12C>T		intron_variant		ENST00000262304.9	NP_001009944.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PKD1	ENST00000262304.9	c.8161+12C>T		intron_variant		1	NM_001009944.3	ENSP00000262304	P5

Frequencies

GnomAD3 genomes AF: 0.00107 AC: 159 AN: 148118 Hom.: 2 Cov.: 20

Gnomad AFR AF: 0.00318

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000666

Gnomad ASJ AF: 0.00290

Gnomad EAS AF: 0.000812

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000119

Gnomad OTH AF: 0.00146

GnomAD3 exomes AF: 0.000441 AC: 67 AN: 151966 Hom.: 0 AF XY: 0.000412 AC XY: 34 AN XY: 82430

Gnomad AFR exome AF: 0.00426

Gnomad AMR exome AF: 0.0000788

Gnomad ASJ exome AF: 0.00156

Gnomad EAS exome AF: 0.0000828

Gnomad SAS exome AF: 0.000342

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000132

Gnomad OTH exome AF: 0.000686

GnomAD4 exome AF: 0.000298 AC: 405 AN: 1359084 Hom.: 5 Cov.: 28 AF XY: 0.000296 AC XY: 199 AN XY: 673434

Gnomad4 AFR exome AF: 0.00458

Gnomad4 AMR exome AF: 0.000191

Gnomad4 ASJ exome AF: 0.00229

Gnomad4 EAS exome AF: 0.000136

Gnomad4 SAS exome AF: 0.000214

Gnomad4 FIN exome AF: 0.0000237

Gnomad4 NFE exome AF: 0.000136

Gnomad4 OTH exome AF: 0.000618

GnomAD4 genome AF: 0.00112 AC: 166 AN: 148232 Hom.: 2 Cov.: 20 AF XY: 0.00113 AC XY: 82 AN XY: 72342

Gnomad4 AFR AF: 0.00335

Gnomad4 AMR AF: 0.000665

Gnomad4 ASJ AF: 0.00290

Gnomad4 EAS AF: 0.000814

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000119

Gnomad4 OTH AF: 0.00145

Alfa AF: 0.000779 Hom.: 0

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2022	PKD1: BS1, BS2 -
Likely benign, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The PKD1 c.8161+12C>T variant was not identified in the literature. The c.8161+12C>T variant was identified in dbSNP (ID: rs375283810) as “NA” and ADPKD Mutation Database (as likely neutral). The c.8161+12C>T variant was identified in the 1000 Genomes Project in 10 of 5000 chromosomes (frequency: 0.002), NHLBI GO Exome Sequencing Project in 3 of 7768 European American and in 3 of 3774 African American alleles. The variant also was identified in the Exome Aggregation Consortium database (March 14, 2016) in 15 of 18810 chromosomes (freq. 0.0008) in the following populations: European (Non-Finnish) in 8 of 7356 chromosomes (freq. 0.001), African in 5 of 1234 chromosomes (freq. 0.004), South Asian in 1 of 8084 chromosomes (freq. 0.0001), and Other in 1 of 166 chromosomes (freq. 0.006), but was not seen in East Asian, Finnish and Latino populations, increasing the likelihood this could be a low frequency benign variant in some populations. However we cannot be certain that data from control databases is specific to PKD1 and not from one of the six PKD1 pseudogenes. The c.8161+12C>T variant is located in the 5' splice region but does not affect the invariant +1 and +2 positions. 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's criteria to be classified as likely benign. -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Polycystic kidney disease, adult type Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Sep 01, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.33
DANN	Benign	0.83
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: rs375283810; hg19: chr16-2154487;