chr2-232535129-GGA-G
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1_StrongPM2PP3_ModeratePP5_Moderate
The NM_000751.3(CHRND):c.1374_1375del(p.Lys459ArgfsTer113) variant causes a frameshift, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,238 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★).
Frequency
Consequence
NM_000751.3 frameshift, splice_region
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 10 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CHRND | NM_000751.3 | c.1374_1375del | p.Lys459ArgfsTer113 | frameshift_variant, splice_region_variant | 12/12 | ENST00000258385.8 | |
CHRND | NM_001256657.2 | c.1329_1330del | p.Lys444ArgfsTer113 | frameshift_variant, splice_region_variant | 11/11 | ||
CHRND | NM_001311195.2 | c.792_793del | p.Lys265ArgfsTer113 | frameshift_variant, splice_region_variant | 10/10 | ||
CHRND | NM_001311196.2 | c.1071_1072del | p.Lys358ArgfsTer113 | frameshift_variant, splice_region_variant | 12/12 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CHRND | ENST00000258385.8 | c.1374_1375del | p.Lys459ArgfsTer113 | frameshift_variant, splice_region_variant | 12/12 | 1 | NM_000751.3 | P1 | |
CHRND | ENST00000543200.5 | c.1329_1330del | p.Lys444ArgfsTer113 | frameshift_variant, splice_region_variant | 11/11 | 2 | |||
CHRND | ENST00000441621.6 | c.*556_*557del | splice_region_variant, 3_prime_UTR_variant, NMD_transcript_variant | 11/11 | 5 | ||||
CHRND | ENST00000446616.1 | c.*1015_*1016del | splice_region_variant, 3_prime_UTR_variant, NMD_transcript_variant | 12/12 | 3 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152238Hom.: 0 Cov.: 33
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152238Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 74384
ClinVar
Submissions by phenotype
Lethal multiple pterygium syndrome Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Knight Diagnostic Laboratories, Oregon Health and Sciences University | Mar 24, 2016 | The c.1374_1375delGA (p. Lys459Argfs*113) frameshift variant in the CHRND gene has not been previously reported. This variant is predicted to result in the loss of a stop codon or loss of the splice acceptor site in the last exon of this gene, which contains a ligand-gated ion channel domain. Multiple in silico algorithms predict this variant to have a deleterious effect (GERP=5.13, Human Splicing Finder v3.0 predicts creation of a new splice acceptor). This variant is absent from the population databases (Exome Sequencing Project; 1000 Genomes; and ExAC). One family with multiple affected individuals that are compound heterozygous for a nonsense variant (p.Arg464*), which is downstream of this variant and a missense variant (p.Phe74Leu) has been reported (Michalk et al., 2008). Therefore, this collective evidence supports the classification of c.1374_1375delGA (p. Lys459Argfs*113) as a Likely pathogenic variant for Lethal Multiple Pterygium Syndrome. We have confirmed this finding in our laboratory using Sanger sequencing. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at