rs1554221478

Positions:

• chr6-51754927-TCTA-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PM4_Supporting PP5

The NM_138694.4(PKHD1):​c.8651_8653del​(p.Val2884del) variant causes a inframe deletion change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. V2884V) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PKHD1 NM_138694.4 inframe_deletion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:1
• Conservation: PhyloP100: 5.71

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_138694.4. Strenght limited to Supporting due to length of the change: 1aa.
• PP5: Variant 6-51754927-TCTA-T is Pathogenic according to our data. Variant chr6-51754927-TCTA-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 553349.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Likely_pathogenic=1}. Variant chr6-51754927-TCTA-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PKHD1	NM_138694.4	c.8651_8653del	p.Val2884del	inframe_deletion	56/67	ENST00000371117.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PKHD1	ENST00000371117.8	c.8651_8653del	p.Val2884del	inframe_deletion	56/67	1	NM_138694.4	P2
PKHD1	ENST00000340994.4	c.8651_8653del	p.Val2884del	inframe_deletion	56/61	5		A2

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Autosomal recessive polycystic kidney disease Pathogenic:2 Uncertain:1

Likely pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Aug 10, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Aug 23, 2017	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Invitae	Aug 10, 2018	In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Experimental studies and prediction algorithms are not available for this variant, and the functional significance of the deleted amino acids is currently unknown. This variant has been observed on the opposite chromosome (in trans) from a pathogenic variant in an individual affected with polycystic kidney disease (PMID: 15698423, Invitae). This finding is consistent with autosomal recessive inheritance, and suggests that this variant contributes to disease. This variant is not present in population databases (ExAC no frequency). This variant, c.8651_8653delTAG, results in the deletion of 1 amino acid(s) of the PKHD1 protein (p.Val2884del), but otherwise preserves the integrity of the reading frame. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1554221478; hg19: chr6-51619725;