6-52035697-C-T

Variant names:

• chr6-52035697-C-T
• rs794727466
• NM_138694.4:c.3122G>A

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM2 PP3_Strong PP5

The NM_138694.4(PKHD1):​c.3122G>A​(p.Gly1041Asp) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: PKHD1 NM_138694.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:5
• Conservation: PhyloP100: 4.91
• Publications: 1 publications found

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]

PKHD1 Gene-Disease associations (from GenCC):

• autosomal recessive polycystic kidney disease

  Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Myriad Women’s Health, Orphanet
• polycystic kidney disease 4

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, Laboratory for Molecular Medicine, Genomics England PanelApp
• Caroli disease

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.99
• PP5: Variant 6-52035697-C-T is Pathogenic according to our data. Variant chr6-52035697-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 196145.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PKHD1	NM_138694.4	c.3122G>A	p.Gly1041Asp	missense_variant	Exon 28 of 67	ENST00000371117.8	NP_619639.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PKHD1	ENST00000371117.8	c.3122G>A	p.Gly1041Asp	missense_variant	Exon 28 of 67	1	NM_138694.4	ENSP00000360158.3
PKHD1	ENST00000340994.4	c.3122G>A	p.Gly1041Asp	missense_variant	Exon 28 of 61	5		ENSP00000341097.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:1 Uncertain:2

Nov 23, 2015

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 13, 2014

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 05, 2018

Blueprint Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Uncertain:1

May 29, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: PKHD1 c.3122G>A (p.Gly1041Asp) results in a non-conservative amino acid change located in the IPT domain (IPR002909) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251336 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.3122G>A has been reported in the literature in individuals affected with Polycystic Kidney And Hepatic Disease (Burgmaier_2021). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 33940108). ClinVar contains an entry for this variant (Variation ID: 196145). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Autosomal recessive polycystic kidney disease Uncertain:1

Sep 16, 2020

Natera, Inc.

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

PKHD1-related disorder Uncertain:1

May 04, 2024

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The PKHD1 c.3122G>A variant is predicted to result in the amino acid substitution p.Gly1041Asp. This variant has not been reported in a large population database, indicating this variant is rare. This variant has been reported with a suspected pathogenic variant (c.778G>A, p.Glu260Lys) in an individual with autosomal recessive polycystic kidney disease (ARPKD) (Burgmaier et al. 2021. PubMed ID: 33940108, Supplementary table S4). In addition, at PreventionGenetics, this variant has also been found with a pathogenic variant in an individual with suspected ARPKD. Therefore, we highly suspect this variant is pathogenic. At this time, however, 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	Pathogenic	0.88
BayesDel_addAF	Pathogenic	0.51	D
BayesDel_noAF	Pathogenic	0.49
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.89	D;.
Eigen	Pathogenic	0.75
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.81	T;T
M_CAP	Pathogenic	0.65	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.6	M;M
PhyloP100		4.9
PrimateAI	Uncertain	0.52	T
PROVEAN	Pathogenic	-6.1	D;D
REVEL	Pathogenic	0.90
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;D
Vest4		0.94
MutPred		0.88		Loss of catalytic residue at S1043 (P = 0.0949);Loss of catalytic residue at S1043 (P = 0.0949);
MVP		0.98
MPC		0.43
ClinPred		1.0	D
GERP RS		5.6
Varity_R		0.98
gMVP		0.98
Mutation Taster		=12/88	disease causing (ClinVar)

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: rs794727466; hg19: chr6-51900495; COSMIC: COSV61876505;