chr16-2091453-G-C

Variant names:

• chr16-2091453-G-C
• rs567482892
• NM_001009944.3:c.11682C>G

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM1 PM2 PP3_Moderate

The NM_001009944.3(PKD1):​c.11682C>G​(p.Ser3894Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000919 in 1,087,664 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. Synonymous variant affecting the same amino acid position (i.e. S3894S) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 9.2e-7 (0 hom.)
• Consequence: PKD1 NM_001009944.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.86
• 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-AS1 (HGNC:56035): (PKD1 antisense RNA 1)

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 12 uncertain in NM_001009944.3
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.894

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.11682C>G	p.Ser3894Arg	missense	Exon 42 of 46	NP_001009944.3
	PKD1	NM_000296.4		c.11679C>G	p.Ser3893Arg	missense	Exon 42 of 46	NP_000287.4
	PKD1-AS1	NR_135175.1		n.18G>C		non_coding_transcript_exon	Exon 1 of 3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PKD1	ENST00000262304.9	TSL:1 MANE Select	c.11682C>G	p.Ser3894Arg	missense	Exon 42 of 46	ENSP00000262304.4
	PKD1	ENST00000423118.5	TSL:1	c.11679C>G	p.Ser3893Arg	missense	Exon 42 of 46	ENSP00000399501.1
	PKD1	ENST00000485120.1	TSL:3	n.671C>G		non_coding_transcript_exon	Exon 3 of 3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 9.19e-7 AC: 1 AN: 1087664 Hom.: 0 Cov.: 32 AF XY: 0.00000191 AC XY: 1 AN XY: 524328

African (AFR) AF: 0.00 AC: 0 AN: 19750

American (AMR) AF: 0.00 AC: 0 AN: 6562

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 11974

East Asian (EAS) AF: 0.00 AC: 0 AN: 18712

South Asian (SAS) AF: 0.00 AC: 0 AN: 41338

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 24078

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2814

European-Non Finnish (NFE) AF: 0.00000109 AC: 1 AN: 920806

Other (OTH) AF: 0.00 AC: 0 AN: 41630

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.58
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.080
CADD	Benign	17
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.46	T
Eigen	Benign	0.029
Eigen_PC	Benign	-0.13
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.77	T
M_CAP	Pathogenic	0.99	D
MetaRNN	Pathogenic	0.89	D
MetaSVM	Benign	-0.33	T
MutationAssessor	Uncertain	2.6	M
PhyloP100		1.9
PrimateAI	Pathogenic	0.86	D
PROVEAN	Uncertain	-2.5	N
REVEL	Uncertain	0.54
Sift	Uncertain	0.010	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.55
MutPred		0.57		Gain of MoRF binding (P = 0.0153)
MVP		0.91
ClinPred		0.97	D
GERP RS		1.9
Varity_R		0.71
gMVP		0.62
Mutation Taster		=48/52	disease causing

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: rs567482892; hg19: chr16-2141454;