NM_001009944.3:c.11683G>A

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_001009944.3(PKD1):​c.11683G>A​(p.Ala3895Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000184 in 1,086,058 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. Variant has been reported in ClinVar as Uncertain significance (★). 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: 0.000018 (0 hom.)
• Consequence: PKD1 NM_001009944.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -2.41
• Publications: 1 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_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.16668513).

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>A	p.Ala3895Thr	missense	Exon 42 of 46	NP_001009944.3	P98161-1
	PKD1	NM_000296.4		c.11680G>A	p.Ala3894Thr	missense	Exon 42 of 46	NP_000287.4
	PKD1-AS1	NR_135175.1		n.17C>T		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>A	p.Ala3895Thr	missense	Exon 42 of 46	ENSP00000262304.4	P98161-1
	PKD1	ENST00000423118.5	TSL:1	c.11680G>A	p.Ala3894Thr	missense	Exon 42 of 46	ENSP00000399501.1	P98161-3
	PKD1	ENST00000485120.1	TSL:3	n.672G>A		non_coding_transcript_exon	Exon 3 of 3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.0000184 AC: 20 AN: 1086058 Hom.: 0 Cov.: 31 AF XY: 0.0000172 AC XY: 9 AN XY: 523516

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: 0.00 AC: 0 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: 0.0000217 AC: 20 AN: 919986

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

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000189

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Polycystic kidney disease, adult type (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	0.53
DANN	Benign	0.90
DEOGEN2	Benign	0.13	T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.032	N
LIST_S2	Benign	0.61	T
M_CAP	Pathogenic	0.79	D
MetaRNN	Benign	0.17	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	-0.14	N
PhyloP100		-2.4
PrimateAI	Uncertain	0.73	T
PROVEAN	Benign	-0.17	N
REVEL	Benign	0.024
Sift	Benign	1.0	T
Sift4G	Benign	0.66	T
Polyphen		0.068	B
Vest4		0.051
MutPred		0.35		Loss of sheet (P = 0.0104)
MVP		0.50
ClinPred		0.072	T
GERP RS		-7.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.11
gMVP		0.42
Mutation Taster		=88/12	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: rs1200946575; hg19: chr16-2141453;