NM_001009944.3:c.214C>G

Variant names:

• chr16-2135476-G-C
• rs972113626
• NM_001009944.3:c.214C>G

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM1 PM2

The NM_001009944.3(PKD1):​c.214C>G​(p.Leu72Val) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 3/3 splice prediction tools predict no significant impact on normal splicing. 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. L72Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000030 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: PKD1 NM_001009944.3 missense, splice_region
• Scores: Splicing: ADA: 0.00004872
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.31
• 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 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: Uncertain_significance. The variant received 4 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 10 uncertain in NM_001009944.3
• 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PKD1	NM_001009944.3	MANE Select	c.214C>G	p.Leu72Val	missense splice_region	Exon 1 of 46	NP_001009944.3
	PKD1	NM_000296.4		c.214C>G	p.Leu72Val	missense splice_region	Exon 1 of 46	NP_000287.4

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PKD1	ENST00000262304.9	TSL:1 MANE Select	c.214C>G	p.Leu72Val	missense splice_region	Exon 1 of 46	ENSP00000262304.4
	PKD1	ENST00000423118.5	TSL:1	c.214C>G	p.Leu72Val	missense splice_region	Exon 1 of 46	ENSP00000399501.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000295 AC: 3 AN: 1016760 Hom.: 0 Cov.: 20 AF XY: 0.00000209 AC XY: 1 AN XY: 478822

African (AFR) AF: 0.00 AC: 0 AN: 20718

American (AMR) AF: 0.00 AC: 0 AN: 6506

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 11840

East Asian (EAS) AF: 0.00 AC: 0 AN: 21648

South Asian (SAS) AF: 0.000107 AC: 2 AN: 18682

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 18534

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2582

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 876956

Other (OTH) AF: 0.0000254 AC: 1 AN: 39294

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.040
CADD	Benign	20
DANN	Benign	0.81
DEOGEN2	Benign	0.18	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.33	N
LIST_S2	Benign	0.45	T
M_CAP	Pathogenic	1.0	D
MetaRNN	Uncertain	0.49	T
MetaSVM	Uncertain	0.33	D
MutationAssessor	Uncertain	2.9	M
PhyloP100		2.3
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-0.90	N
REVEL	Uncertain	0.38
Sift	Uncertain	0.018	D
Sift4G	Uncertain	0.049	D
Polyphen		0.0	B
Vest4		0.29
MutPred		0.68		Loss of stability (P = 0.146)
MVP		0.78
ClinPred		0.16	T
GERP RS		-3.8
PromoterAI		-0.020	Neutral
Varity_R		0.14
gMVP		0.30
Mutation Taster		=83/17	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000049
dbscSNV1_RF	Benign	0.12
SpliceAI score (max)		0.18		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: rs972113626; hg19: chr16-2185477;