16-2091470-C-A

Position:

• chr16-2091470-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM1 BS2_Supporting

The NM_001009944.3(PKD1):​c.11665G>T​(p.Ala3889Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000161 in 1,179,522 control chromosomes in the GnomAD database, with no homozygous occurrence. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000016 (0 hom.)
• Consequence: PKD1 NM_001009944.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2
• Conservation: PhyloP100: 0.378

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

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM1: In a topological_domain Extracellular (size 214) in uniprot entity PKD1_HUMAN there are 39 pathogenic changes around while only 11 benign (78%) in NM_001009944.3
• BS2: High AC in GnomAdExome4 at 19 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PKD1	NM_001009944.3	c.11665G>T	p.Ala3889Ser	missense_variant	42/46	ENST00000262304.9	NP_001009944.3
PKD1-AS1	NR_135175.1	n.35C>A		non_coding_transcript_exon_variant	1/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PKD1	ENST00000262304.9	c.11665G>T	p.Ala3889Ser	missense_variant	42/46	1	NM_001009944.3	ENSP00000262304	P5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.0000161 AC: 19 AN: 1179522 Hom.: 0 Cov.: 32 AF XY: 0.0000139 AC XY: 8 AN XY: 577026

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000194

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 23, 2022

The c.11662G>T (p.A3888S) alteration is located in exon 42 (coding exon 42) of the PKD1 gene. This alteration results from a G to T substitution at nucleotide position 11662, causing the alanine (A) at amino acid position 3888 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

PKD1-related disorder Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 10, 2024

The PKD1 c.11665G>T variant is predicted to result in the amino acid substitution p.Ala3889Ser. This variant has been reported in an individual with atypical autosomal dominant polycystic kidney disease (Chang et al 2022. PubMed ID: 36573973). This variant is reported in 0.020% of alleles in individuals of South Asian descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.092
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	7.4
DANN	Benign	0.64
DEOGEN2	Benign	0.12	T;.
Eigen	Benign	-0.93
Eigen_PC	Benign	-0.96
FATHMM_MKL	Benign	0.67	D
LIST_S2	Benign	0.75	T;T
M_CAP	Pathogenic	0.81	D
MetaRNN	Uncertain	0.45	T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	1.9	L;.
MutationTaster	Benign	0.99	N;N
PrimateAI	Uncertain	0.71	T
PROVEAN	Benign	0.19	N;N
REVEL	Benign	0.033
Sift	Benign	0.91	T;T
Sift4G	Uncertain	0.047	D;D
Polyphen		0.075	B;B
Vest4		0.15
MutPred		0.41		Gain of phosphorylation at A3889 (P = 0.0183);.;
MVP		0.74
ClinPred		0.041	T
GERP RS		-1.2
Varity_R		0.14
gMVP		0.42

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

Publications

LitVar

Other links and lift over

dbSNP: rs1300036375; hg19: chr16-2141471;