NM_001009944.3:c.8978T>G

Variant names:

• chr16-2102604-A-C
• rs1555450487
• NM_001009944.3:c.8978T>G

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM1 PM2 PM5 PP3_Moderate

The NM_001009944.3(PKD1):​c.8978T>G​(p.Leu2993Arg) variant causes a missense change involving the alteration of a 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 Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L2993Q) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: PKD1 NM_001009944.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.25
• 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: ClinGen, Orphanet
• 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: Likely_pathogenic. The variant received 8 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 10 uncertain in NM_001009944.3
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr16-2102604-A-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 1806504.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.877

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PKD1	NM_001009944.3	MANE Select	c.8978T>G	p.Leu2993Arg	missense	Exon 25 of 46	NP_001009944.3
	PKD1	NM_000296.4		c.8978T>G	p.Leu2993Arg	missense	Exon 25 of 46	NP_000287.4

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PKD1	ENST00000262304.9	TSL:1 MANE Select	c.8978T>G	p.Leu2993Arg	missense	Exon 25 of 46	ENSP00000262304.4
	PKD1	ENST00000423118.5	TSL:1	c.8978T>G	p.Leu2993Arg	missense	Exon 25 of 46	ENSP00000399501.1
	PKD1	ENST00000480227.5	TSL:1	n.715T>G		non_coding_transcript_exon	Exon 3 of 8

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Polycystic kidney disease, adult type (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.040
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.61	D
Eigen	Uncertain	0.29
Eigen_PC	Uncertain	0.29
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Benign	0.77	T
M_CAP	Uncertain	0.23	D
MetaRNN	Pathogenic	0.88	D
MetaSVM	Benign	-0.35	T
MutationAssessor	Uncertain	2.8	M
PhyloP100		8.2
PrimateAI	Uncertain	0.57	T
PROVEAN	Pathogenic	-4.8	D
REVEL	Uncertain	0.48
Sift	Uncertain	0.0030	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.78
MutPred		0.68		Loss of sheet (P = 0.0037)
MVP		0.89
ClinPred		0.97	D
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.76
gMVP		0.87
Mutation Taster		=13/87	disease causing

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: rs1555450487; hg19: chr16-2152605;