rs775061512
Positions:
Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2PP3_StrongPP5
The NM_001013838.3(CARMIL2):c.1916T>A(p.Leu639His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000134 in 1,571,952 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000013 ( 0 hom. )
Consequence
CARMIL2
NM_001013838.3 missense
NM_001013838.3 missense
Scores
11
5
2
Clinical Significance
Conservation
PhyloP100: 8.02
Genes affected
CARMIL2 (HGNC:27089): (capping protein regulator and myosin 1 linker 2) This gene encodes a member of the CARMIL (capping protein, Arp2/3, myosin-I linker) family of proteins. The encoded protein interacts with and negatively regulates the heterodimeric capping protein and promotes cell migration. Reduced expression of this gene has been observed in human psoriasis patients. Mutations in this gene cause a human immunodeficiency syndrome characterized by smooth muscle tumors and impaired T-cell function. [provided by RefSeq, May 2017]
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ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 7 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.943
PP5
?
Variant 16-67649616-T-A is Pathogenic according to our data. Variant chr16-67649616-T-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 565281.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Likely_pathogenic=1}.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CARMIL2 | NM_001013838.3 | c.1916T>A | p.Leu639His | missense_variant | 20/38 | ENST00000334583.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CARMIL2 | ENST00000334583.11 | c.1916T>A | p.Leu639His | missense_variant | 20/38 | 1 | NM_001013838.3 | A2 |
Frequencies
GnomAD3 genomes ? AF: 0.0000133 AC: 2AN: 150654Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000451 AC: 10AN: 221730Hom.: 0 AF XY: 0.0000163 AC XY: 2AN XY: 122896
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GnomAD4 exome AF: 0.0000134 AC: 19AN: 1421298Hom.: 0 Cov.: 35 AF XY: 0.00000424 AC XY: 3AN XY: 707124
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GnomAD4 genome ? AF: 0.0000133 AC: 2AN: 150654Hom.: 0 Cov.: 32 AF XY: 0.0000136 AC XY: 1AN XY: 73574
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:2Uncertain:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Severe combined immunodeficiency due to CARMIL2 deficiency Pathogenic:2
Likely pathogenic, criteria provided, single submitter | curation | SIB Swiss Institute of Bioinformatics | Jan 08, 2019 | This variant is interpreted as a Likely pathogenic for Immunodeficiency 58, autosomal recessive. The following ACMG Tag(s) were applied: PM2 : Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. PP3 : Multiple lines of computational evidence support a deleterious effect on the gene or gene product. PP1 : Cosegregation with disease in multiple affected family members in a gene definitively known to cause the disease (PMID:27896283). PM1 : Located in a mutational hot spot and/or critical and well-established functional domain (e.g., active site of an enzyme) without benign variation. - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Sep 28, 2018 | - - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Nov 29, 2021 | In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 565281). This missense change has been observed in individual(s) with clinical features of primary immunodeficiency (PMID: 27896283). This variant is present in population databases (rs775061512, gnomAD 0.01%). This sequence change replaces leucine, which is neutral and non-polar, with histidine, which is basic and polar, at codon 639 of the CARMIL2 protein (p.Leu639His). - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Uncertain
D;.
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Benign
T;T
M_CAP
Uncertain
D
MetaRNN
Pathogenic
D;D
MetaSVM
Uncertain
D
MutationTaster
Benign
D;D
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D;D
REVEL
Pathogenic
Sift
Pathogenic
D;D
Sift4G
Pathogenic
D;D
Polyphen
D;.
Vest4
MutPred
Loss of stability (P = 0.0072);.;
MVP
MPC
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at