rs376987651

Variant names:

• chr6-52084933-T-C
• rs376987651
• NM_138694.4:c.1A>G

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_138694.4(PKHD1):​c.1A>G​(p.Met1?) variant causes a start lost change. The variant allele was found at a frequency of 0.00000346 in 1,445,866 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 Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000035 (0 hom.)
• Consequence: PKHD1 NM_138694.4 start_lost
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 3.75
• Publications: 6 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: Pathogenic. The variant received 18 ACMG points.

• PVS1: Start lost variant, next in-frame start position is after 8 pathogenic variants. Next in-frame start position is after 9 codons. Genomic position: 52084909. Lost 0.002 part of the original CDS.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 6-52084933-T-C is Pathogenic according to our data. Variant chr6-52084933-T-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 550469.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PKHD1	NM_138694.4	c.1A>G	p.Met1?	start_lost	Exon 2 of 67	ENST00000371117.8	NP_619639.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PKHD1	ENST00000371117.8	c.1A>G	p.Met1?	start_lost	Exon 2 of 67	1	NM_138694.4	ENSP00000360158.3
PKHD1	ENST00000340994.4	c.1A>G	p.Met1?	start_lost	Exon 2 of 61	5		ENSP00000341097.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.0000119 AC: 3 AN: 251326 AF XY: 0.0000221

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000264

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000346 AC: 5 AN: 1445866 Hom.: 0 Cov.: 27 AF XY: 0.00000555 AC XY: 4 AN XY: 720456

African (AFR) AF: 0.00 AC: 0 AN: 33170

American (AMR) AF: 0.00 AC: 0 AN: 44696

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26006

East Asian (EAS) AF: 0.00 AC: 0 AN: 39578

South Asian (SAS) AF: 0.00 AC: 0 AN: 85950

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53402

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5730

European-Non Finnish (NFE) AF: 0.00000456 AC: 5 AN: 1097522

Other (OTH) AF: 0.00 AC: 0 AN: 59812

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000312 Hom.: 0

Bravo AF: 0.00000756

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000247 AC: 3

EpiCase AF: 0.0000545

EpiControl AF: 0.000178

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Polycystic kidney disease 4 Pathogenic:2

Jan 26, 2017

Counsyl

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

Oct 26, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Polycystic kidney disease Pathogenic:1

-

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The PKHD1 p.Met1? variant was identified in 3 of 260 proband chromosomes (frequency: 0.0115) from individuals or families with Autosomal Recessive PKD (Melchionda, 2016). The affected individuals found to carry the p.Met? variant were descried as perinatal (alive), 8 year old, and neonatal demise (Melchionda, 2016). The variant was also identified in dbSNP (ID: rs376987651) as NA, and LOVD 3.0 databases. The variant was not identified in ClinVar, GeneInsight-COGR, RWTH AAachen University ARPKD databases. The variant was identified in control databases in 4 of 246088 chromosomes at a frequency of 0.000016 (Genome Aggregation Consortium Feb 27, 2017). The c.1A>G variant occurs in the first base of the exon. The c.1A>G p.Met1? variant occurs in the first base of the translation initiation site (the Methionine amino acid start site), increasing the likelihood this variant may disrupt translation or lead to an abnormal protein product. In summary, based on the above information, this variant meets our laboratory’s criteria to be classified as pathogenic. -

Autosomal recessive polycystic kidney disease Pathogenic:1

Jan 09, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change affects the initiator methionine of the PKHD1 mRNA. The next in-frame methionine is located at codon 9. This variant is present in population databases (rs376987651, gnomAD 0.004%). Disruption of the initiator codon has been observed in individual(s) with autosomal recessive polycystic kidney disease (PMID: 27225849). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 550469). This variant disrupts a region of the PKHD1 protein in which other variant(s) (p.Leu8Pro) have been observed in individuals with PKHD1-related conditions (Invitae). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.31
CADD	Benign	17
DANN	Benign	0.92
DEOGEN2	Benign	0.16	T;.
Eigen	Benign	-0.068
Eigen_PC	Benign	-0.026
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.90	D;D
M_CAP	Pathogenic	0.91	D
MetaRNN	Pathogenic	0.96	D;D
MetaSVM	Benign	-0.42	T
PhyloP100		3.8
PROVEAN	Benign	-1.7	N;N
REVEL	Uncertain	0.62
Sift	Pathogenic	0.0	D;D
Sift4G	Benign	0.49	T;T
Polyphen		0.30	B;B
Vest4		0.91
MVP		0.92
ClinPred		0.99	D
GERP RS		5.0
Varity_R		0.87
gMVP		0.69
Mutation Taster		=22/178	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: rs376987651; hg19: chr6-51949731;