chr16-2114843-A-C

Position:

• chr16-2114843-A-C

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PS1_Moderate PM2 PM5 PP3_Moderate PP5

The ENST00000262304.9(PKD1):​c.2180T>G​(p.Leu727Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000000769 in 1,300,450 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L727Q) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.7e-7 (0 hom.)
• Consequence: PKD1 ENST00000262304.9 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1
• Conservation: PhyloP100: 5.42

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

• PS1: Transcript ENST00000262304.9 (PKD1) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in UniProt
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr16-2114843-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 562302.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.865
• PP5: Variant 16-2114843-A-C is Pathogenic according to our data. Variant chr16-2114843-A-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 994718.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=1}. Variant chr16-2114843-A-C is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PKD1	NM_001009944.3	c.2180T>G	p.Leu727Arg	missense_variant	11/46	ENST00000262304.9	NP_001009944.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PKD1	ENST00000262304.9	c.2180T>G	p.Leu727Arg	missense_variant	11/46	1	NM_001009944.3	ENSP00000262304	P5
PKD1	ENST00000423118.5	c.2180T>G	p.Leu727Arg	missense_variant	11/46	1		ENSP00000399501	A2
PKD1	ENST00000488185.2	c.472+2646T>G		intron_variant		5		ENSP00000456672
PKD1	ENST00000568591.5	c.*508T>G		3_prime_UTR_variant, NMD_transcript_variant	7/12	2		ENSP00000457162

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.69e-7 AC: 1 AN: 1300450 Hom.: 0 Cov.: 25 AF XY: 0.00000155 AC XY: 1 AN XY: 645642

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: 0.0000129

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

PKD1-related disorder Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 12, 2023

The PKD1 c.2180T>G variant is predicted to result in the amino acid substitution p.Leu727Arg. This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. The p.Leu727 residue is highly conserved during evolution from frog to human. This variant has been reported in an individual with polycystic kidney disease (Hoefele et al. 2010. PubMed ID: 21115670). In addition, we have found this variant in the heterozygous state in three presumably unrelated patients tested for polycystic kidney disease at PreventionGenetics. Of note, different substitutions at this codon have been reported in individuals with polycystic kidney disease (Human Gene Mutation Database - HGMD; https://pkdb.mayo.edu/variants). This variant is interpreted as likely pathogenic. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Athena Diagnostics

Jan 09, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.69
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Uncertain	0.13
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.72	D;.
Eigen	Uncertain	0.44
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.74	T;T
M_CAP	Pathogenic	0.83	D
MetaRNN	Pathogenic	0.86	D;D
MetaSVM	Benign	-0.40	T
MutationAssessor	Uncertain	2.7	M;M
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.60	T
PROVEAN	Uncertain	-3.2	D;D
REVEL	Uncertain	0.36
Sift	Uncertain	0.0010	D;D
Sift4G	Uncertain	0.0020	D;D
Polyphen		1.0	D;D
Vest4		0.83
MutPred		0.42		Gain of methylation at L727 (P = 0.0377);Gain of methylation at L727 (P = 0.0377);
MVP		0.90
ClinPred		0.96	D
GERP RS		5.2
Varity_R		0.57
gMVP		0.93

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: rs1616940; hg19: chr16-2164844;