16-2135616-C-T

Variant names:

• chr16-2135616-C-T
• rs972049140
• NM_001009944.3:c.74G>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001009944.3(PKD1):​c.74G>A​(p.Gly25Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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. G25V) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000024 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: PKD1 NM_001009944.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.77
• 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.026694626).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PKD1	NM_001009944.3	c.74G>A	p.Gly25Asp	missense_variant	Exon 1 of 46	ENST00000262304.9	NP_001009944.3
PKD1	NM_000296.4	c.74G>A	p.Gly25Asp	missense_variant	Exon 1 of 46		NP_000287.4
PKD1	XM_047434208.1	c.74G>A	p.Gly25Asp	missense_variant	Exon 1 of 48		XP_047290164.1
PKD1	XM_047434209.1	c.74G>A	p.Gly25Asp	missense_variant	Exon 1 of 47		XP_047290165.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PKD1	ENST00000262304.9	c.74G>A	p.Gly25Asp	missense_variant	Exon 1 of 46	1	NM_001009944.3	ENSP00000262304.4
PKD1	ENST00000423118.5	c.74G>A	p.Gly25Asp	missense_variant	Exon 1 of 46	1		ENSP00000399501.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000239 AC: 2 AN: 835192 Hom.: 0 Cov.: 16 AF XY: 0.00000258 AC XY: 1 AN XY: 388076

African (AFR) AF: 0.00 AC: 0 AN: 15710

American (AMR) AF: 0.00 AC: 0 AN: 1646

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 5512

East Asian (EAS) AF: 0.00 AC: 0 AN: 4182

South Asian (SAS) AF: 0.00 AC: 0 AN: 17004

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 2516

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1666

European-Non Finnish (NFE) AF: 0.00000263 AC: 2 AN: 759042

Other (OTH) AF: 0.00 AC: 0 AN: 27914

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.68
CADD	Benign	7.7
DANN	Benign	0.78
DEOGEN2	Benign	0.14	T;.
Eigen	Benign	-2.3
Eigen_PC	Benign	-2.3
FATHMM_MKL	Benign	0.0042	N
LIST_S2	Benign	0.26	T;T
M_CAP	Benign	0.020	T
MetaRNN	Benign	0.027	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.69	N;N
PhyloP100		-1.8
PrimateAI	Pathogenic	0.82	D
PROVEAN	Benign	0.060	N;N
REVEL	Benign	0.018
Sift	Benign	0.92	T;T
Sift4G	Benign	0.88	T;T
Polyphen		0.0	B;B
Vest4		0.12
MutPred		0.29		Loss of methylation at R28 (P = 0.0483);Loss of methylation at R28 (P = 0.0483);
MVP		0.30
ClinPred		0.040	T
GERP RS		-6.1
PromoterAI		-0.070	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.6
Varity_R		0.052
gMVP		0.33
Mutation Taster		=84/16	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: rs972049140; hg19: chr16-2185617;