NM_003632.3:c.2901_2902delCT
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_003632.3(CNTNAP1):c.2901_2902delCT(p.Cys968PhefsTer11) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000217 in 1,614,120 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_003632.3 frameshift
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
CNTNAP1 | ENST00000264638.9 | c.2901_2902delCT | p.Cys968PhefsTer11 | frameshift_variant | Exon 18 of 24 | 1 | NM_003632.3 | ENSP00000264638.3 | ||
CNTNAP1 | ENST00000591662.1 | n.*662_*663delCT | non_coding_transcript_exon_variant | Exon 18 of 24 | 1 | ENSP00000466571.1 | ||||
CNTNAP1 | ENST00000591662.1 | n.*662_*663delCT | 3_prime_UTR_variant | Exon 18 of 24 | 1 | ENSP00000466571.1 | ||||
ENSG00000267765 | ENST00000592440.1 | n.363+5658_363+5659delAG | intron_variant | Intron 1 of 1 | 2 |
Frequencies
GnomAD3 genomes AF: 0.0000460 AC: 7AN: 152226Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000199 AC: 5AN: 251486Hom.: 0 AF XY: 0.0000294 AC XY: 4AN XY: 135918
GnomAD4 exome AF: 0.0000192 AC: 28AN: 1461894Hom.: 0 AF XY: 0.0000179 AC XY: 13AN XY: 727248
GnomAD4 genome AF: 0.0000460 AC: 7AN: 152226Hom.: 0 Cov.: 32 AF XY: 0.0000672 AC XY: 5AN XY: 74364
ClinVar
Submissions by phenotype
not provided Pathogenic:3
For these reasons, this variant has been classified as Pathogenic. This sequence change creates a premature translational stop signal (p.Cys968Phefs*11) in the CNTNAP1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CNTNAP1 are known to be pathogenic (PMID: 24319099). This variant is present in population databases (rs751050956, ExAC 0.004%). This variant has been observed in individual(s) with CNTNAP1-related conditions (PMID: 24319099, 31397905). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 204313). -
Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at a significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 31397905, 28374019, 24319099, 34930662, 33820833, 31618753) -
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Lethal congenital contracture syndrome 7 Pathogenic:3
This frameshifting variant is predicted to result in a premature stop codon and is therefore considered a loss-of-function mutation. This variant has been previously reported as a homozygous change in three siblings with arthrogryposis, hypotonia, respiratory distress, and feeding difficulties (PMID: 24319099). It is present as a heterozygous change in the gnomAD population database at a frequency of 0.003% (7/277236). Based on the available evidence, the c.2901_2902delCT (p.Cys968PhefsTer11) variant is classified as a pathogenic change. -
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ACMG codes:PVS1; PM2; PM3; PP1S -
Neuropathy, congenital hypomyelinating, 3 Pathogenic:3
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Variant summary: CNTNAP1 c.2901_2902delCT (p.Cys968PhefsX11) results in a premature termination codon, predicted to cause absence of the protein due to nonsense mediated decay, which is a commonly known mechanism for disease. The variant allele was found at a frequency of 2e-05 in 251486 control chromosomes (gnomAD). c.2901_2902delCT has been reported in the literature in an individual(s) affected with Neuropathy, Congenital Hypomyelinating, 3 who was compound heterozygous with a pathogenic gross deletion variant (Bowling_2022). The following publication has been ascertained in the context of this evaluation (PMID: 34930662). Five submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
The c.2901_2902del;p.(Cys968Phefs*11) is a null frameshift variant (NMD) in the CNTNAP1 gene and predicts alteration of the nonsense-mediate decay - NMD is present in a relevantexon to the transcript -PVS1. This sequence change has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 204313; OMIM: 602346.0003; PMID: 24319099) - PS4_moderate. This variant is not present in population databases (rs751050956, gnomAD; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2. The p.(Cys968Phefs*11) was detected in trans with a pathogenic variant (PMID: 24319099) - PM3.The variant co-segregated with disease in multiple affected family members (PMID: 24319099) - PP1_strong. In summary, the currently available evidence indicates that the variant is pathogenic. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at