16-2090802-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001009944.3(PKD1):c.12010C>G(p.Gln4004Glu) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,460,124 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: PKD1 NM_001009944.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.79

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.849

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PKD1	NM_001009944.3	c.12010C>G	p.Gln4004Glu	missense_variant	44/46	ENST00000262304.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PKD1	ENST00000262304.9	c.12010C>G	p.Gln4004Glu	missense_variant	44/46	1	NM_001009944.3	P5
PKD1	ENST00000423118.5	c.12007C>G	p.Gln4003Glu	missense_variant	44/46	1		A2
PKD1	ENST00000472577.1	n.38C>G		non_coding_transcript_exon_variant	1/3	2
PKD1	ENST00000564313.1	n.531C>G		non_coding_transcript_exon_variant	3/3	4

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD3 exomes AF: 0.00000409 AC: 1 AN: 244454 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 133320

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000923

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1460124 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 726386

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 34

ExAC AF: 0.00000827 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Uncertain	0.032	T
BayesDel_noAF	Benign	-0.19
Cadd	Uncertain	24
Dann	Uncertain	0.99
DEOGEN2	Benign	0.28	T;.
Eigen	Uncertain	0.23
Eigen_PC	Benign	0.12
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.84	T;T
M_CAP	Pathogenic	0.54	D
MetaRNN	Pathogenic	0.85	D;D
MetaSVM	Uncertain	-0.26	T
MutationAssessor	Uncertain	2.6	M;.
MutationTaster	Benign	0.98	D;D
PrimateAI	Pathogenic	0.81	D
PROVEAN	Benign	-0.99	N;N
REVEL	Uncertain	0.42
Sift	Benign	0.082	T;T
Sift4G	Pathogenic	0.0	D;D
Polyphen		0.98	D;D
Vest4		0.55
MutPred		0.55		Loss of MoRF binding (P = 0.0286);.;
MVP		0.84
ClinPred		0.84	D
GERP RS		3.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.49
gMVP		0.36

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

Publications

LitVar

Other links and lift over

dbSNP: rs766551411; hg19: chr16-2140803;