16-67647603-G-T
Variant summary
Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_001013838.3(CARMIL2):c.871+1G>T variant causes a splice donor, intron change. The variant allele was found at a frequency of 0.00000124 in 1,609,250 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).
Frequency
Consequence
NM_001013838.3 splice_donor, intron
Scores
Clinical Significance
Conservation
Publications
- severe combined immunodeficiency due to CARMIL2 deficiencyInheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P, Orphanet
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ACMG classification
Our verdict: Pathogenic. The variant received 18 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152100Hom.: 0 Cov.: 32 show subpopulations
GnomAD4 exome AF: 6.86e-7 AC: 1AN: 1457150Hom.: 0 Cov.: 34 AF XY: 0.00000138 AC XY: 1AN XY: 724322 show subpopulations
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152100Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74298 show subpopulations
ClinVar
Submissions by phenotype
Severe combined immunodeficiency due to CARMIL2 deficiency Pathogenic:3
Splice site variant in the CARMIL2 gene (c.871+1G>T), affecting the invariant +1 position of the donor splice site, which is critical for proper mRNA processing. This alteration is predicted to abolish normal splicing, likely resulting in exon skipping or use of a cryptic splice site, leading to a nonfunctional protein. The variant is absent from population databases (PM2) and has been reported in at least one individual with clinical features consistent with autosomal recessive CARMIL2 deficiency, which includes combined immunodeficiency and EBV-related disease. In silico tools support a deleterious impact (PP3), and clinical phenotype matches gene-disease association (PP4). Sanger sequencing confirmed variant presence. Classified as Pathogenic. Meets ACMG criteria: PVS1 (canonical splice site), PM2 (absent from controls), PP3 (in silico), PP4 (phenotype specificity). -
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The invariant splice donor c.871+1G>T in CARMIL2 gene has been reported in homozygous state in individualss affected with primary immunodeficiency disorders Schober T, et.al., 2017. The c.871+1G>T variant is absent in gnomAD Exomes. This variant has been reported to the ClinVar database as Pathogenic. Splice AI predicts this variant to cause splice donor loss 0.99 and splice donor gain 0.61. Loss of function variants have been previously reported to be disease causing. For these reasons, this variant has been classified as Pathogenic. -
Combined immunodeficiency Pathogenic:1
Experimentally proven primary immunodeficiency; combined immunodeficiency -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at