rs112387277

Variant names:

• chr16-2090911-G-C
• rs112387277
• NM_001009944.3:c.11976C>G

Your query was ambiguous. Multiple possible variants found:

• chr16-2090911-G-C
• chr16-2090911-G-A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001009944.3(PKD1):​c.11976C>G​(p.Ala3992Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00528 in 1,592,700 control chromosomes in the GnomAD database, including 42 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0032 (4 hom., cov: 34)
  • Exomes 𝑓: 0.0055 (38 hom.)
• Consequence: PKD1 NM_001009944.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 0.169
• Publications: 3 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: Orphanet, ClinGen
• 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.73).
• BP6: Variant 16-2090911-G-C is Benign according to our data. Variant chr16-2090911-G-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 256912.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.169 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00322 (491/152372) while in subpopulation NFE AF = 0.00562 (382/68024). AF 95% confidence interval is 0.00515. There are 4 homozygotes in GnomAd4. There are 206 alleles in the male GnomAd4 subpopulation. Median coverage is 34. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 4 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.11976C>G	p.Ala3992Ala	synonymous	Exon 43 of 46	NP_001009944.3	P98161-1
	PKD1	NM_000296.4		c.11973C>G	p.Ala3991Ala	synonymous	Exon 43 of 46	NP_000287.4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PKD1	ENST00000262304.9	TSL:1 MANE Select	c.11976C>G	p.Ala3992Ala	synonymous	Exon 43 of 46	ENSP00000262304.4	P98161-1
	PKD1	ENST00000423118.5	TSL:1	c.11973C>G	p.Ala3991Ala	synonymous	Exon 43 of 46	ENSP00000399501.1	P98161-3
	PKD1	ENST00000561668.5	TSL:3	n.*500C>G		non_coding_transcript_exon	Exon 4 of 4	ENSP00000461391.1	I3L4N0

Frequencies

GnomAD3 genomes AF: 0.00322 AC: 491 AN: 152254 Hom.: 4 Cov.: 34

Gnomad AFR AF: 0.00118

Gnomad AMI AF: 0.0110

Gnomad AMR AF: 0.00190

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00186

Gnomad FIN AF: 0.000376

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00562

Gnomad OTH AF: 0.00382

GnomAD2 exomes AF: 0.00302 AC: 617 AN: 204404 AF XY: 0.00288

Gnomad AFR exome AF: 0.00100

Gnomad AMR exome AF: 0.00205

Gnomad ASJ exome AF: 0.000436

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00119

Gnomad NFE exome AF: 0.00507

Gnomad OTH exome AF: 0.00343

GnomAD4 exome AF: 0.00550 AC: 7915 AN: 1440328 Hom.: 38 Cov.: 34 AF XY: 0.00533 AC XY: 3818 AN XY: 716472

African (AFR) AF: 0.000781 AC: 26 AN: 33288

American (AMR) AF: 0.00180 AC: 78 AN: 43258

Ashkenazi Jewish (ASJ) AF: 0.000580 AC: 15 AN: 25858

East Asian (EAS) AF: 0.0000254 AC: 1 AN: 39350

South Asian (SAS) AF: 0.00162 AC: 138 AN: 85214

European-Finnish (FIN) AF: 0.00133 AC: 53 AN: 39882

Middle Eastern (MID) AF: 0.00104 AC: 6 AN: 5746

European-Non Finnish (NFE) AF: 0.00663 AC: 7344 AN: 1107860

Other (OTH) AF: 0.00424 AC: 254 AN: 59872

GnomAD4 genome AF: 0.00322 AC: 491 AN: 152372 Hom.: 4 Cov.: 34 AF XY: 0.00276 AC XY: 206 AN XY: 74504

African (AFR) AF: 0.00118 AC: 49 AN: 41598

American (AMR) AF: 0.00189 AC: 29 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00186 AC: 9 AN: 4832

European-Finnish (FIN) AF: 0.000376 AC: 4 AN: 10632

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00562 AC: 382 AN: 68024

Other (OTH) AF: 0.00378 AC: 8 AN: 2116

Alfa AF: 0.000794 Hom.: 0

Bravo AF: 0.00324

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not provided (6)
-	-	1	Autosomal dominant polycystic kidney disease (1)
-	-	1	not specified (1)
-	-	1	Polycystic kidney disease (1)
-	-	1	Polycystic kidney disease, adult type (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.73
CADD	Benign	2.5
DANN	Benign	0.54
PhyloP100		0.17
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	polymorphism

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: rs112387277; hg19: chr16-2140912;