rs1554217929

Variant names:

• chr6-52058610-AA-GT
• rs1554217929
• NM_138694.4:c.1234-10_1234-9delTTinsAC

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP6

The NM_138694.4(PKHD1):​c.1234-10_1234-9delTTinsAC variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type MNV, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: PKHD1 NM_138694.4 intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: 1.63
• Publications: 0 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_benign. The variant received -1 ACMG points.

• BP6: Variant 6-52058610-AA-GT is Benign according to our data. Variant chr6-52058610-AA-GT is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 458590.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PKHD1	NM_138694.4	c.1234-10_1234-9delTTinsAC		intron_variant	Intron 15 of 66	ENST00000371117.8	NP_619639.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PKHD1	ENST00000371117.8	c.1234-10_1234-9delTTinsAC		intron_variant	Intron 15 of 66	1	NM_138694.4	ENSP00000360158.3
PKHD1	ENST00000340994.4	c.1234-10_1234-9delTTinsAC		intron_variant	Intron 15 of 60	5		ENSP00000341097.4

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: Uncertain:1 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1

Nov 08, 2024

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In silico analysis is inconclusive as to whether the variant alters gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown; Has not been previously published as pathogenic or benign to our knowledge -

not specified Benign:1

Jan 06, 2025

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

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: PKHD1 c.1234-10_1234-9delinsAC alters a nucleotide located at a position not widely known to affect splicing. Several computational tools predict a significant impact on normal splicing: One predict the variant abolishes a 3' acceptor site. Two predict the variant weakens a 3 acceptor site. However, these predictions have yet to be confirmed by functional studies. Additionally, a different splice predictor tool predicts the variant to have no impact on splicing (Splice-AI). The variant allele was found at a frequency of 0.0008 in 1613584 control chromosomes, predominantly at a frequency of 0.0011 within the Non-Finnish European subpopulation in the gnomAD database, including 1 homozygotes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.1234-10_1234-9delinsAC in individuals affected with Polycystic Kidney And Hepatic Disease and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 458590). Based on the evidence outlined above, the variant was classified as likely benign. -

Autosomal recessive polycystic kidney disease Benign:1

Jul 08, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.6

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1554217929; hg19: chr6-51923408;