chr16-2112452-C-T

Variant names:

• chr16-2112452-C-T
• rs148727945
• NM_001009944.3:c.3183G>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.3183G>A​(p.Glu1061Glu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0027 in 1,588,386 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0016 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0028 (12 hom.)
• Consequence: PKD1 NM_001009944.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -0.407
• 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: 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

ENSG00000261240 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.76).
• BP6: Variant 16-2112452-C-T is Benign according to our data. Variant chr16-2112452-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 256945.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.407 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0016 (244/152322) while in subpopulation NFE AF = 0.00268 (182/68012). AF 95% confidence interval is 0.00236. There are 1 homozygotes in GnomAd4. There are 109 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 12 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.3183G>A	p.Glu1061Glu	synonymous	Exon 14 of 46	NP_001009944.3	P98161-1
	PKD1	NM_000296.4		c.3183G>A	p.Glu1061Glu	synonymous	Exon 14 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.3183G>A	p.Glu1061Glu	synonymous	Exon 14 of 46	ENSP00000262304.4	P98161-1
	PKD1	ENST00000423118.5	TSL:1	c.3183G>A	p.Glu1061Glu	synonymous	Exon 14 of 46	ENSP00000399501.1	P98161-3
	PKD1	ENST00000483024.1	TSL:5	c.63G>A	p.Glu21Glu	synonymous	Exon 2 of 5	ENSP00000456670.1	H3BSE8

Frequencies

GnomAD3 genomes AF: 0.00160 AC: 244 AN: 152204 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000676

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00111

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000753

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00268

Gnomad OTH AF: 0.00382

GnomAD2 exomes AF: 0.00153 AC: 291 AN: 190260 AF XY: 0.00152

Gnomad AFR exome AF: 0.000403

Gnomad AMR exome AF: 0.00159

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00263

Gnomad OTH exome AF: 0.00236

GnomAD4 exome AF: 0.00282 AC: 4048 AN: 1436064 Hom.: 12 Cov.: 32 AF XY: 0.00268 AC XY: 1911 AN XY: 714122

African (AFR) AF: 0.000603 AC: 20 AN: 33180

American (AMR) AF: 0.00146 AC: 64 AN: 43794

Ashkenazi Jewish (ASJ) AF: 0.0000386 AC: 1 AN: 25914

East Asian (EAS) AF: 0.000101 AC: 4 AN: 39530

South Asian (SAS) AF: 0.0000235 AC: 2 AN: 85000

European-Finnish (FIN) AF: 0.000430 AC: 16 AN: 37218

Middle Eastern (MID) AF: 0.000243 AC: 1 AN: 4116

European-Non Finnish (NFE) AF: 0.00339 AC: 3760 AN: 1107590

Other (OTH) AF: 0.00301 AC: 180 AN: 59722

GnomAD4 genome AF: 0.00160 AC: 244 AN: 152322 Hom.: 1 Cov.: 33 AF XY: 0.00146 AC XY: 109 AN XY: 74484

African (AFR) AF: 0.000674 AC: 28 AN: 41572

American (AMR) AF: 0.00111 AC: 17 AN: 15306

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

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.000753 AC: 8 AN: 10618

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

European-Non Finnish (NFE) AF: 0.00268 AC: 182 AN: 68012

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

Alfa AF: 0.00226 Hom.: 0

Bravo AF: 0.00167

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not provided (5)
-	-	2	not specified (2)
-	-	2	Polycystic kidney disease, adult type (2)
-	-	1	Polycystic kidney disease (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
CADD	Benign	4.9
DANN	Benign	0.74
PhyloP100		-0.41
PromoterAI		0.0085	Neutral
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: rs148727945; hg19: chr16-2162453;