16-2116608-G-C

Variant names:

• chr16-2116608-G-C
• rs768613812
• NM_001009944.3:c.1643C>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001009944.3(PKD1):​c.1643C>G​(p.Ala548Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000071 in 1,408,340 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 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. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A548V) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: PKD1 NM_001009944.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.849
• 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.1229575).

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.1643C>G	p.Ala548Gly	missense	Exon 8 of 46	NP_001009944.3
	PKD1	NM_000296.4		c.1643C>G	p.Ala548Gly	missense	Exon 8 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.1643C>G	p.Ala548Gly	missense	Exon 8 of 46	ENSP00000262304.4
	PKD1	ENST00000423118.5	TSL:1	c.1643C>G	p.Ala548Gly	missense	Exon 8 of 46	ENSP00000399501.1
	PKD1	ENST00000568591.5	TSL:2	n.574C>G		non_coding_transcript_exon	Exon 4 of 12	ENSP00000457162.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.10e-7 AC: 1 AN: 1408340 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 697888

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 32348

American (AMR) AF: 0.00 AC: 0 AN: 39594

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25434

East Asian (EAS) AF: 0.00 AC: 0 AN: 37430

South Asian (SAS) AF: 0.00 AC: 0 AN: 81028

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40636

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4090

European-Non Finnish (NFE) AF: 9.18e-7 AC: 1 AN: 1089352

Other (OTH) AF: 0.00 AC: 0 AN: 58428

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.091
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.64
CADD	Benign	12
DANN	Benign	0.70
DEOGEN2	Benign	0.21	T
Eigen	Benign	-0.78
Eigen_PC	Benign	-0.90
FATHMM_MKL	Benign	0.037	N
LIST_S2	Benign	0.68	T
M_CAP	Uncertain	0.13	D
MetaRNN	Benign	0.12	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		-0.85
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-0.64	N
REVEL	Benign	0.033
Sift	Benign	0.15	T
Sift4G	Benign	0.39	T
Polyphen		0.53	P
Vest4		0.22
MutPred		0.21		Loss of stability (P = 0.0737)
MVP		0.57
ClinPred		0.15	T
GERP RS		-0.069
Varity_R		0.038
gMVP		0.54
Mutation Taster		=69/31	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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: rs768613812; hg19: chr16-2166609;