7-16421269-C-CA
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_001101426.4(CRPPA):βc.53_54insTβ(p.Ser19GlufsTer97) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000114 in 1,296,758 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (β β ). Synonymous variant affecting the same amino acid position (i.e. L18L) has been classified as Likely benign.
Frequency
Consequence
NM_001101426.4 frameshift
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CRPPA | NM_001101426.4 | c.53_54insT | p.Ser19GlufsTer97 | frameshift_variant | 1/10 | ENST00000407010.7 | |
LOC105375168 | XR_007060223.1 | n.297+288dup | intron_variant, non_coding_transcript_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CRPPA | ENST00000407010.7 | c.53_54insT | p.Ser19GlufsTer97 | frameshift_variant | 1/10 | 5 | NM_001101426.4 | P1 | |
CRPPA | ENST00000399310.3 | c.53_54insT | p.Ser19GlufsTer97 | frameshift_variant | 1/9 | 1 | |||
CRPPA | ENST00000674759.1 | c.-46-14933_-46-14932insT | intron_variant | ||||||
CRPPA | ENST00000675257.1 | c.-46-14933_-46-14932insT | intron_variant |
Frequencies
GnomAD3 genomes AF: 0.000119 AC: 18AN: 151810Hom.: 0 Cov.: 33
GnomAD4 exome AF: 0.000114 AC: 130AN: 1144948Hom.: 0 Cov.: 32 AF XY: 0.0000912 AC XY: 50AN XY: 547966
GnomAD4 genome AF: 0.000119 AC: 18AN: 151810Hom.: 0 Cov.: 33 AF XY: 0.0000944 AC XY: 7AN XY: 74160
ClinVar
Submissions by phenotype
not provided Pathogenic:4
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | May 09, 2018 | The c.53dupT pathogenic variant in the ISPD gene has been previously reported in individuals with ISPD-related disorders who harbor an additional ISPD variant (Roscioli et al., 2012; Cirak et al., 2013). The c.53dupT variant causes a frameshift starting with codon Serine 19, changes this amino acid to a Glutamic acid residue and creates a premature Stop codon at position 97 of the new reading frame, denoted p.Ser19GlufsX97. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The c.53dupT variant is not observed at a significant frequency in individuals undergoing testing at GeneDx. Therefore, we interpret c.53dupT as a pathogenic variant. - |
Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Jun 25, 2018 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Aug 26, 2022 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Athena Diagnostics | Sep 21, 2021 | This variant is expected to result in the loss of a functional protein. The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). - |
not specified Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Apr 08, 2021 | The c.53dupT (p.S19Efs*97) alteration, located in exon 1 (coding exon 1) of the ISPD gene, consists of a duplication of T at position 53, causing a translational frameshift with a predicted alternate stop codon after 97 amino acids. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. Based on the available evidence, this alteration is classified as pathogenic. - |
Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A, 7;C5190987:Autosomal recessive limb-girdle muscular dystrophy type 2U Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jul 21, 2023 | For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 279985). This premature translational stop signal has been observed in individuals with Walker-Warburg syndrome or autosomal recessive limb girdle muscular dystrophy with intellectual disability (PMID: 2328832, 22522421). This variant is present in population databases (no rsID available, gnomAD 0.006%). This sequence change creates a premature translational stop signal (p.Ser19Glufs*97) in the ISPD gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ISPD are known to be pathogenic (PMID: 23288328). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at