16-2091451-G-C

Variant names:

• chr16-2091451-G-C
• rs1251469390
• NM_001009944.3:c.11684C>G

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001009944.3(PKD1):​c.11684C>G​(p.Ala3895Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000243 in 1,232,312 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 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. A3895V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 33)
  • Exomes 𝑓: 9.2e-7 (0 hom.)
• Consequence: PKD1 NM_001009944.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.192
• 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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3666639).

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.11684C>G	p.Ala3895Gly	missense	Exon 42 of 46	NP_001009944.3	P98161-1
	PKD1	NM_000296.4		c.11681C>G	p.Ala3894Gly	missense	Exon 42 of 46	NP_000287.4
	PKD1-AS1	NR_135175.1		n.16G>C		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.11684C>G	p.Ala3895Gly	missense	Exon 42 of 46	ENSP00000262304.4	P98161-1
	PKD1	ENST00000423118.5	TSL:1	c.11681C>G	p.Ala3894Gly	missense	Exon 42 of 46	ENSP00000399501.1	P98161-3
	PKD1	ENST00000485120.1	TSL:3	n.673C>G		non_coding_transcript_exon	Exon 3 of 3

Frequencies

GnomAD3 genomes AF: 0.0000134 AC: 2 AN: 149002 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000299

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 9.23e-7 AC: 1 AN: 1083310 Hom.: 0 Cov.: 31 AF XY: 0.00000192 AC XY: 1 AN XY: 521920

⚠️ 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: 19664

American (AMR) AF: 0.00 AC: 0 AN: 6422

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 11800

East Asian (EAS) AF: 0.00 AC: 0 AN: 18450

South Asian (SAS) AF: 0.00 AC: 0 AN: 40698

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 23878

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2788

European-Non Finnish (NFE) AF: 0.00000109 AC: 1 AN: 918208

Other (OTH) AF: 0.00 AC: 0 AN: 41402

⚠️ 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 AF: 0.0000134 AC: 2 AN: 149002 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 72600

African (AFR) AF: 0.00 AC: 0 AN: 41074

American (AMR) AF: 0.00 AC: 0 AN: 15000

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3422

East Asian (EAS) AF: 0.00 AC: 0 AN: 5148

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9414

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.0000299 AC: 2 AN: 66840

Other (OTH) AF: 0.00 AC: 0 AN: 2048

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.080
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	7.9
DANN	Benign	0.68
DEOGEN2	Benign	0.13	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.099	N
LIST_S2	Benign	0.54	T
M_CAP	Pathogenic	0.93	D
MetaRNN	Benign	0.37	T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	1.4	L
PhyloP100		0.19
PrimateAI	Uncertain	0.74	T
PROVEAN	Benign	0.19	N
REVEL	Benign	0.15
Sift	Benign	0.090	T
Sift4G	Benign	0.23	T
Polyphen		0.032	B
Vest4		0.14
MutPred		0.44		Gain of helix (P = 0.0078)
MVP		0.54
ClinPred		0.071	T
GERP RS		1.9
Varity_R		0.13
gMVP		0.44
Mutation Taster		=87/13	polymorphism

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: rs1251469390; hg19: chr16-2141452;