rs375283810

Variant names:

• chr16-2104486-G-A
• rs375283810
• NM_001009944.3:c.8161+12C>T

Your query was ambiguous. Multiple possible variants found:

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

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001009944.3(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 NM_001009944.3 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.673
• Publications: 0 publications found

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]

PKD1 Gene-Disease associations (from GenCC):

• autosomal dominant polycystic kidney disease

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• polycystic kidney disease 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Laboratory for Molecular Medicine, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• autosomal recessive polycystic kidney disease

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• Caroli disease

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp

ACMG classification

Our verdict: Benign. The variant received -20 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 Benign/Likely_benign. ClinVar VariationId is 257012.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00112 (166/148232) while in subpopulation AFR AF = 0.00335 (131/39160). AF 95% confidence interval is 0.00288. There are 2 homozygotes in GnomAd4. There are 82 alleles in the male GnomAd4 subpopulation. Median coverage is 20. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PKD1	NM_001009944.3	c.8161+12C>T		intron_variant	Intron 22 of 45	ENST00000262304.9	NP_001009944.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PKD1	ENST00000262304.9	c.8161+12C>T		intron_variant	Intron 22 of 45	1	NM_001009944.3	ENSP00000262304.4

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

GnomAD2 exomes AF: 0.000441 AC: 67 AN: 151966 AF XY: 0.000412

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 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

African (AFR) AF: 0.00458 AC: 137 AN: 29942

American (AMR) AF: 0.000191 AC: 7 AN: 36614

Ashkenazi Jewish (ASJ) AF: 0.00229 AC: 57 AN: 24882

East Asian (EAS) AF: 0.000136 AC: 5 AN: 36718

South Asian (SAS) AF: 0.000214 AC: 17 AN: 79304

European-Finnish (FIN) AF: 0.0000237 AC: 1 AN: 42114

Middle Eastern (MID) AF: 0.000746 AC: 3 AN: 4024

European-Non Finnish (NFE) AF: 0.000136 AC: 143 AN: 1048872

Other (OTH) AF: 0.000618 AC: 35 AN: 56614

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

African (AFR) AF: 0.00335 AC: 131 AN: 39160

American (AMR) AF: 0.000665 AC: 10 AN: 15040

Ashkenazi Jewish (ASJ) AF: 0.00290 AC: 10 AN: 3444

East Asian (EAS) AF: 0.000814 AC: 4 AN: 4914

South Asian (SAS) AF: 0.00 AC: 0 AN: 4670

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10492

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 288

European-Non Finnish (NFE) AF: 0.000119 AC: 8 AN: 67244

Other (OTH) AF: 0.00145 AC: 3 AN: 2076

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

-

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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. -

Jul 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PKD1: BS1, BS2 -

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Polycystic kidney disease, adult type Benign:1

Sep 01, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.33
DANN	Benign	0.83
PhyloP100		-0.67
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

Other links and lift over

dbSNP: rs375283810; hg19: chr16-2154487;