16-2100510-G-C

Variant names:

• chr16-2100510-G-C
• rs776866974
• NM_001009944.3:c.9454C>G

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1 PM2 PP3_Moderate PP5_Moderate

The NM_001009944.3(PKD1):​c.9454C>G​(p.Arg3152Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. R3152R) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PKD1 NM_001009944.3 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 1.17

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 Likely_pathogenic. Variant got 8 ACMG points.

• PM1: In a domain PLAT (size 115) in uniprot entity PKD1_HUMAN there are 30 pathogenic changes around while only 9 benign (77%) in NM_001009944.3
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.932
• PP5: Variant 16-2100510-G-C is Pathogenic according to our data. Variant chr16-2100510-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 974539.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PKD1	NM_001009944.3	c.9454C>G	p.Arg3152Gly	missense_variant	Exon 27 of 46	ENST00000262304.9	NP_001009944.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PKD1	ENST00000262304.9	c.9454C>G	p.Arg3152Gly	missense_variant	Exon 27 of 46	1	NM_001009944.3	ENSP00000262304.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Polycystic kidney disease, adult type Pathogenic:1

Feb 01, 2020

Molecular Biology Laboratory, Fundació Puigvert

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.72
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.20
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.66	D;.
Eigen	Pathogenic	0.71
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.89	D;D
M_CAP	Pathogenic	0.68	D
MetaRNN	Pathogenic	0.93	D;D
MetaSVM	Uncertain	0.21	D
MutationAssessor	Pathogenic	3.5	H;H
PrimateAI	Uncertain	0.62	T
PROVEAN	Pathogenic	-5.6	D;D
REVEL	Uncertain	0.63
Sift	Uncertain	0.0040	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;D
Vest4		0.90
MutPred		0.70		Loss of stability (P = 0.037);Loss of stability (P = 0.037);
MVP		0.95
ClinPred		0.99	D
GERP RS		4.5
Varity_R		0.97
gMVP		0.91

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: rs776866974; hg19: chr16-2150511;