chr16-2091452-C-G

Variant names:

• chr16-2091452-C-G
• rs1200946575
• NM_001009944.3:c.11683G>C

Variant summary

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

The NM_001009944.3(PKD1):​c.11683G>C​(p.Ala3895Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000921 in 1,086,058 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. A3895V) has been classified as Uncertain significance.

• 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: -2.41
• 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: 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PKD1	NM_001009944.3	MANE Select	c.11683G>C	p.Ala3895Pro	missense	Exon 42 of 46	NP_001009944.3	P98161-1
	PKD1	NM_000296.4		c.11680G>C	p.Ala3894Pro	missense	Exon 42 of 46	NP_000287.4
	PKD1-AS1	NR_135175.1		n.17C>G		non_coding_transcript_exon	Exon 1 of 3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PKD1	ENST00000262304.9	TSL:1 MANE Select	c.11683G>C	p.Ala3895Pro	missense	Exon 42 of 46	ENSP00000262304.4	P98161-1
	PKD1	ENST00000423118.5	TSL:1	c.11680G>C	p.Ala3894Pro	missense	Exon 42 of 46	ENSP00000399501.1	P98161-3
	PKD1	ENST00000485120.1	TSL:3	n.672G>C		non_coding_transcript_exon	Exon 3 of 3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 9.21e-7 AC: 1 AN: 1086058 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 523516

⚠️ 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: 19702

American (AMR) AF: 0.00 AC: 0 AN: 6484

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 11888

East Asian (EAS) AF: 0.00 AC: 0 AN: 18590

South Asian (SAS) AF: 0.0000244 AC: 1 AN: 41054

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 23974

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2802

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 919986

Other (OTH) AF: 0.00 AC: 0 AN: 41578

⚠️ 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	0.14
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	9.2
DANN	Benign	0.92
DEOGEN2	Benign	0.23	T
Eigen	Benign	-0.96
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.71	T
M_CAP	Pathogenic	0.97	D
MetaRNN	Uncertain	0.52	D
MetaSVM	Benign	-0.70	T
MutationAssessor	Benign	1.7	L
PhyloP100		-2.4
PrimateAI	Uncertain	0.75	T
PROVEAN	Benign	-1.1	N
REVEL	Uncertain	0.31
Sift	Benign	0.096	T
Sift4G	Benign	0.11	T
Polyphen		0.92	P
Vest4		0.29
MutPred		0.55		Gain of loop (P = 0.0079)
MVP		0.75
ClinPred		0.55	D
GERP RS		-7.9
Varity_R		0.51
gMVP		0.69
Mutation Taster		=86/14	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1200946575; hg19: chr16-2141453;