chr16-2105961-G-C

Variant names:

• chr16-2105961-G-C
• rs555499745
• NM_001009944.3:c.7767C>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001009944.3(PKD1):​c.7767C>G​(p.His2589Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000276 in 1,447,920 control chromosomes in the GnomAD database, with no homozygous occurrence. 14/22 in silico tools predict a benign 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. H2589H) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000028 (0 hom.)
• Consequence: PKD1 NM_001009944.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.443
• 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.7767C>G	p.His2589Gln	missense	Exon 20 of 46	NP_001009944.3
	PKD1	NM_000296.4		c.7767C>G	p.His2589Gln	missense	Exon 20 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.7767C>G	p.His2589Gln	missense	Exon 20 of 46	ENSP00000262304.4
	PKD1	ENST00000423118.5	TSL:1	c.7767C>G	p.His2589Gln	missense	Exon 20 of 46	ENSP00000399501.1
	PKD1	ENST00000415938.7	TSL:5	n.1012C>G		non_coding_transcript_exon	Exon 6 of 17

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000425 AC: 1 AN: 235400 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000291

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000276 AC: 4 AN: 1447920 Hom.: 0 Cov.: 34 AF XY: 0.00000139 AC XY: 1 AN XY: 720568

African (AFR) AF: 0.0000300 AC: 1 AN: 33388

American (AMR) AF: 0.0000224 AC: 1 AN: 44700

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26116

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86160

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 42092

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4134

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1111526

Other (OTH) AF: 0.00 AC: 0 AN: 60110

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	8.7
DANN	Benign	0.61
DEOGEN2	Benign	0.16	T
Eigen	Benign	-0.60
Eigen_PC	Benign	-0.76
FATHMM_MKL	Benign	0.44	N
LIST_S2	Benign	0.63	T
M_CAP	Pathogenic	0.68	D
MetaRNN	Uncertain	0.69	D
MetaSVM	Benign	-0.82	T
MutationAssessor	Benign	1.9	M
PhyloP100		0.44
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-0.61	N
REVEL	Benign	0.22
Sift	Benign	0.28	T
Sift4G	Benign	0.066	T
Polyphen		0.94	P
Vest4		0.41
MutPred		0.64		Gain of relative solvent accessibility (P = 0.09)
MVP		0.83
ClinPred		0.16	T
GERP RS		0.57
Varity_R		0.033
gMVP		0.31
Mutation Taster		=56/44	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs555499745; hg19: chr16-2155962;