16-2090679-T-C

Variant names:

• chr16-2090679-T-C
• rs10960
• NM_001009944.3:c.12133A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001009944.3(PKD1):​c.12133A>G​(p.Ile4045Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.191 in 1,611,784 control chromosomes in the GnomAD database, including 37,119 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I4045F) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.29 (9035 hom., cov: 34)
  • Exomes 𝑓: 0.18 (28084 hom.)
• Consequence: PKD1 NM_001009944.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.239
• Publications: 40 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=8.577714E-5).
• BP6: Variant 16-2090679-T-C is Benign according to our data. Variant chr16-2090679-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 256913.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.573 is higher than 0.05.

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.12133A>G	p.Ile4045Val	missense	Exon 44 of 46	NP_001009944.3	P98161-1
	PKD1	NM_000296.4		c.12130A>G	p.Ile4044Val	missense	Exon 44 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.12133A>G	p.Ile4045Val	missense	Exon 44 of 46	ENSP00000262304.4	P98161-1
	PKD1	ENST00000423118.5	TSL:1	c.12130A>G	p.Ile4044Val	missense	Exon 44 of 46	ENSP00000399501.1	P98161-3
	PKD1	ENST00000472577.1	TSL:2	n.161A>G		non_coding_transcript_exon	Exon 1 of 3

Frequencies

GnomAD3 genomes AF: 0.288 AC: 43759 AN: 152030 Hom.: 9006 Cov.: 34

Gnomad AFR AF: 0.579

Gnomad AMI AF: 0.0976

Gnomad AMR AF: 0.203

Gnomad ASJ AF: 0.254

Gnomad EAS AF: 0.00154

Gnomad SAS AF: 0.0922

Gnomad FIN AF: 0.231

Gnomad MID AF: 0.269

Gnomad NFE AF: 0.179

Gnomad OTH AF: 0.261

GnomAD2 exomes AF: 0.181 AC: 44565 AN: 245684 AF XY: 0.175

Gnomad AFR exome AF: 0.581

Gnomad AMR exome AF: 0.122

Gnomad ASJ exome AF: 0.255

Gnomad EAS exome AF: 0.000275

Gnomad FIN exome AF: 0.222

Gnomad NFE exome AF: 0.183

Gnomad OTH exome AF: 0.190

GnomAD4 exome AF: 0.181 AC: 263811 AN: 1459636 Hom.: 28084 Cov.: 36 AF XY: 0.177 AC XY: 128525 AN XY: 726110

African (AFR) AF: 0.585 AC: 19562 AN: 33462

American (AMR) AF: 0.131 AC: 5864 AN: 44676

Ashkenazi Jewish (ASJ) AF: 0.261 AC: 6804 AN: 26108

East Asian (EAS) AF: 0.000302 AC: 12 AN: 39696

South Asian (SAS) AF: 0.0950 AC: 8193 AN: 86240

European-Finnish (FIN) AF: 0.221 AC: 11402 AN: 51540

Middle Eastern (MID) AF: 0.236 AC: 1361 AN: 5766

European-Non Finnish (NFE) AF: 0.179 AC: 198819 AN: 1111798

Other (OTH) AF: 0.195 AC: 11794 AN: 60350

GnomAD4 genome AF: 0.288 AC: 43838 AN: 152148 Hom.: 9035 Cov.: 34 AF XY: 0.285 AC XY: 21189 AN XY: 74386

African (AFR) AF: 0.579 AC: 24044 AN: 41502

American (AMR) AF: 0.203 AC: 3099 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.254 AC: 881 AN: 3472

East Asian (EAS) AF: 0.00155 AC: 8 AN: 5170

South Asian (SAS) AF: 0.0921 AC: 445 AN: 4832

European-Finnish (FIN) AF: 0.231 AC: 2449 AN: 10598

Middle Eastern (MID) AF: 0.272 AC: 80 AN: 294

European-Non Finnish (NFE) AF: 0.179 AC: 12199 AN: 67962

Other (OTH) AF: 0.258 AC: 544 AN: 2108

Alfa AF: 0.196 Hom.: 5547

Bravo AF: 0.298

TwinsUK AF: 0.185 AC: 687

ALSPAC AF: 0.176 AC: 680

ESP6500AA AF: 0.556 AC: 2428

ESP6500EA AF: 0.187 AC: 1605

ExAC AF: 0.188 AC: 22643

Asia WGS AF: 0.0790 AC: 277 AN: 3478

EpiCase AF: 0.192

EpiControl AF: 0.194

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.71	T
BayesDel_noAF	Benign	-0.65
CADD	Benign	0.042
DANN	Benign	0.53
DEOGEN2	Benign	0.14	T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.013	N
LIST_S2	Benign	0.22	T
MetaRNN	Benign	0.000086	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	-0.98	N
PhyloP100		-0.24
PrimateAI	Benign	0.47	T
PROVEAN	Benign	0.0	N
REVEL	Benign	0.058
Sift	Benign	0.33	T
Sift4G	Benign	1.0	T
Polyphen		0.0020	B
Vest4		0.052
ClinPred		0.0043	T
GERP RS		-1.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.082
gMVP		0.22
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs10960; hg19: chr16-2140680; COSMIC: COSV51916387; COSMIC: COSV51916387;