chr2-42048839-G-T
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Variant summary
Our verdict is Pathogenic. Variant got 22 ACMG points: 22P and 0B. PVS1PM2PP3_StrongPP5_Very_Strong
The NM_138370.3(PKDCC):c.639+1G>T variant causes a splice donor change. The variant allele was found at a frequency of 0.00000617 in 1,457,592 control chromosomes in the GnomAD database, with no homozygous occurrence. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 31)
Exomes 𝑓: 0.0000061 ( 0 hom. )
Consequence
PKDCC
NM_138370.3 splice_donor
NM_138370.3 splice_donor
Scores
4
2
1
Splicing: ADA: 1.000
2
Clinical Significance
Conservation
PhyloP100: 4.23
Genes affected
PKDCC (HGNC:25123): (protein kinase domain containing, cytoplasmic) Enables non-membrane spanning protein tyrosine kinase activity. Involved in peptidyl-tyrosine phosphorylation and skeletal system development. Located in extracellular region. [provided by Alliance of Genome Resources, Apr 2022]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 22 ACMG points.
PVS1
Splicing variant, LoF is a know mechanism of disease, Cryptic splice site detected, with MaxEntScore 4.8, offset of 22, new splice context is: gggGTaacg. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
PM2
Very rare variant in population databases, with high coverage;
PP3
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
PP5
Variant 2-42048839-G-T is Pathogenic according to our data. Variant chr2-42048839-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 522098.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PKDCC | NM_138370.3 | c.639+1G>T | splice_donor_variant | ENST00000294964.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PKDCC | ENST00000294964.6 | c.639+1G>T | splice_donor_variant | 1 | NM_138370.3 | P1 | |||
PKDCC | ENST00000401498.6 | c.497+1G>T | splice_donor_variant, NMD_transcript_variant | 5 | |||||
PKDCC | ENST00000485578.1 | n.260+1G>T | splice_donor_variant, non_coding_transcript_variant | 2 | |||||
PKDCC | ENST00000492861.1 | n.65+1G>T | splice_donor_variant, non_coding_transcript_variant | 2 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152186Hom.: 0 Cov.: 31
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GnomAD3 exomes AF: 0.0000378 AC: 6AN: 158918Hom.: 0 AF XY: 0.0000345 AC XY: 3AN XY: 86940
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GnomAD4 exome AF: 0.00000613 AC: 8AN: 1305406Hom.: 0 Cov.: 33 AF XY: 0.00000781 AC XY: 5AN XY: 640114
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GnomAD4 genome AF: 0.00000657 AC: 1AN: 152186Hom.: 0 Cov.: 31 AF XY: 0.0000134 AC XY: 1AN XY: 74350
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Inborn genetic diseases Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Oct 06, 2017 | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jul 12, 2023 | Disruption of this splice site has been observed in individuals with clinical features of PKDCC-related skeletal dysplasia (PMID: 30478137; Invitae). This sequence change affects a donor splice site in intron 1 of the PKDCC gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in PKDCC are known to be pathogenic (PMID: 19097194, 30478137). This variant is present in population databases (rs763243200, gnomAD 0.03%). ClinVar contains an entry for this variant (Variation ID: 522098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. - |
Rhizomelic limb shortening with dysmorphic features Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Apr 25, 2023 | - - |
Computational scores
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Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
MutationTaster
Benign
D
GERP RS
Splicing
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dbscSNV1_ADA
Pathogenic
dbscSNV1_RF
Pathogenic
SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_DL_spliceai
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Find out detailed SpliceAI scores and Pangolin per-transcript scores at