6-52071009-T-G

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1 PM2 PM5 PP5

The NM_138694.4(PKHD1):c.664A>C(p.Ile222Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000000698 in 1,432,278 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I222V) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 29)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: PKHD1 NM_138694.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1
• Conservation: PhyloP100: 4.44

Genes affected

PKHD1 (HGNC:9016): (PKHD1 ciliary IPT domain containing fibrocystin/polyductin) The protein encoded by this gene is predicted to have a single transmembrane (TM)-spanning domain and multiple copies of an immunoglobulin-like plexin-transcription-factor domain. Alternative splicing results in two transcript variants encoding different isoforms. Other alternatively spliced transcripts have been described, but the full length sequences have not been determined. Several of these transcripts are predicted to encode truncated products which lack the TM and may be secreted. Mutations in this gene cause autosomal recessive polycystic kidney disease, also known as polycystic kidney and hepatic disease-1. [provided by RefSeq, Jul 2008]

LOC124901327 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 3 uncertain in NM_138694.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr6-52071009-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 406891.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP5: Variant 6-52071009-T-G is Pathogenic according to our data. Variant chr6-52071009-T-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1371356.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PKHD1	NM_138694.4	c.664A>C	p.Ile222Leu	missense_variant	9/67	ENST00000371117.8
LOC124901327	XR_007059606.1	n.7T>G		non_coding_transcript_exon_variant	1/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PKHD1	ENST00000371117.8	c.664A>C	p.Ile222Leu	missense_variant	9/67	1	NM_138694.4	P2
PKHD1	ENST00000340994.4	c.664A>C	p.Ile222Leu	missense_variant	9/61	5		A2

Frequencies

GnomAD3 genomes Cov.: 29

GnomAD4 exome AF: 6.98e-7 AC: 1 AN: 1432278 Hom.: 0 Cov.: 27 AF XY: 0.00000140 AC XY: 1 AN XY: 714758

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: 9.22e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 29

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Polycystic kidney disease 4 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Oct 13, 2023

- -

Autosomal recessive polycystic kidney disease Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Sep 01, 2021

This sequence change replaces isoleucine with leucine at codon 222 of the PKHD1 protein (p.Ile222Leu). The isoleucine residue is moderately conserved and there is a small physicochemical difference between isoleucine and leucine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals affected with PKHD1-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). This variant disrupts the p.Ile222 amino acid residue in PKHD1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 11919560, 12506140, 12846734, 15698423). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.010
Cadd	Benign	20
Dann	Benign	0.97
DEOGEN2	Benign	0.32	T;.
Eigen	Benign	-0.11
Eigen_PC	Benign	-0.069
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.78	T;T
M_CAP	Uncertain	0.11	D
MetaRNN	Uncertain	0.67	D;D
MetaSVM	Benign	-0.36	T
MutationAssessor	Uncertain	2.5	M;M
MutationTaster	Benign	0.64	N;N
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-1.4	N;N
REVEL	Uncertain	0.52
Sift	Pathogenic	0.0	D;D
Sift4G	Benign	0.088	T;T
Polyphen		0.77	P;B
Vest4		0.67
MutPred		0.54		Loss of catalytic residue at I222 (P = 0.177);Loss of catalytic residue at I222 (P = 0.177);
MVP		0.92
MPC		0.13
ClinPred		0.96	D
GERP RS		5.2
Varity_R		0.45
gMVP		0.78

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.12		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: rs369925690; hg19: chr6-51935807;