rs77566834

Variant names:

• chr16-2089712-C-T
• rs77566834
• NM_001009944.3:c.*15G>A

Your query was ambiguous. Multiple possible variants found:

• chr16-2089712-C-T
• chr16-2089712-C-A
• chr16-2089712-C-G

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.*15G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0124 in 1,566,408 control chromosomes in the GnomAD database, including 192 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.012 (18 hom., cov: 34)
  • Exomes 𝑓: 0.012 (174 hom.)
• Consequence: PKD1 NM_001009944.3 3_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.541
• Publications: 2 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]

TSC2 (HGNC:12363): (TSC complex subunit 2) This gene is a tumor suppressor gene that encodes the growth inhibitory protein tuberin. Tuberin interacts with hamartin to form the TSC protein complex which functions in the control of cell growth. This TSC protein complex negatively regulates mammalian target of rapamycin complex 1 (mTORC1) signaling which is a major regulator of anabolic cell growth. Mutations in this gene have been associated with tuberous sclerosis and lymphangioleiomyomatosis. [provided by RefSeq, May 2022]

TSC2 Gene-Disease associations (from GenCC):

• tuberous sclerosis

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• tuberous sclerosis 2

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, G2P, Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine, Ambry Genetics
• lymphangioleiomyomatosis

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• tuberous sclerosis complex

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 16-2089712-C-T is Benign according to our data. Variant chr16-2089712-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 256884.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.0123 (1875/152364) while in subpopulation AMR AF = 0.0188 (288/15304). AF 95% confidence interval is 0.017. There are 18 homozygotes in GnomAd4. There are 1049 alleles in the male GnomAd4 subpopulation. Median coverage is 34. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 18 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001009944.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PKD1	NM_001009944.3	MANE Select	c.*15G>A		3_prime_UTR	Exon 46 of 46	NP_001009944.3	P98161-1
	PKD1	NM_000296.4		c.*15G>A		3_prime_UTR	Exon 46 of 46	NP_000287.4
	TSC2	NM_000548.5	MANE Select	c.*1102C>T		downstream_gene	N/A	NP_000539.2	P49815-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PKD1	ENST00000262304.9	TSL:1 MANE Select	c.*15G>A		3_prime_UTR	Exon 46 of 46	ENSP00000262304.4	P98161-1
	PKD1	ENST00000423118.5	TSL:1	c.*15G>A		3_prime_UTR	Exon 46 of 46	ENSP00000399501.1	P98161-3
	PKD1	ENST00000472577.1	TSL:2	n.955G>A		non_coding_transcript_exon	Exon 3 of 3

Frequencies

GnomAD3 genomes AF: 0.0123 AC: 1875 AN: 152246 Hom.: 18 Cov.: 34

Gnomad AFR AF: 0.00224

Gnomad AMI AF: 0.00877

Gnomad AMR AF: 0.0188

Gnomad ASJ AF: 0.0392

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00331

Gnomad FIN AF: 0.0407

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0126

Gnomad OTH AF: 0.0191

GnomAD2 exomes AF: 0.0144 AC: 2495 AN: 173144 AF XY: 0.0135

Gnomad AFR exome AF: 0.00211

Gnomad AMR exome AF: 0.0104

Gnomad ASJ exome AF: 0.0470

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0412

Gnomad NFE exome AF: 0.0136

Gnomad OTH exome AF: 0.0170

GnomAD4 exome AF: 0.0124 AC: 17521 AN: 1414044 Hom.: 174 Cov.: 31 AF XY: 0.0121 AC XY: 8442 AN XY: 698910

African (AFR) AF: 0.00192 AC: 63 AN: 32742

American (AMR) AF: 0.0104 AC: 382 AN: 36894

Ashkenazi Jewish (ASJ) AF: 0.0458 AC: 1159 AN: 25296

East Asian (EAS) AF: 0.0000265 AC: 1 AN: 37804

South Asian (SAS) AF: 0.00335 AC: 270 AN: 80656

European-Finnish (FIN) AF: 0.0380 AC: 1860 AN: 48936

Middle Eastern (MID) AF: 0.0232 AC: 99 AN: 4262

European-Non Finnish (NFE) AF: 0.0119 AC: 12934 AN: 1088884

Other (OTH) AF: 0.0129 AC: 753 AN: 58570

GnomAD4 genome AF: 0.0123 AC: 1875 AN: 152364 Hom.: 18 Cov.: 34 AF XY: 0.0141 AC XY: 1049 AN XY: 74504

African (AFR) AF: 0.00224 AC: 93 AN: 41592

American (AMR) AF: 0.0188 AC: 288 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.0392 AC: 136 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00331 AC: 16 AN: 4832

European-Finnish (FIN) AF: 0.0407 AC: 432 AN: 10624

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.0126 AC: 859 AN: 68034

Other (OTH) AF: 0.0189 AC: 40 AN: 2116

Alfa AF: 0.0125 Hom.: 4

Bravo AF: 0.0101

Asia WGS AF: 0.00433 AC: 15 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Autosomal dominant polycystic kidney disease (2)
-	-	2	not specified (2)
-	-	1	not provided (1)
-	-	1	Polycystic kidney disease, adult type (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	2.2
DANN	Benign	0.58
PhyloP100		0.54
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

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: rs77566834; hg19: chr16-2139713;