16-67647603-G-T
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Variant summary
Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PVS1PM2PP3_StrongPP5
The NM_001013838.3(CARMIL2):c.871+1G>T variant causes a splice donor 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 (no stars).
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 6.9e-7 ( 0 hom. )
Consequence
CARMIL2
NM_001013838.3 splice_donor
NM_001013838.3 splice_donor
Scores
4
2
1
Splicing: ADA: 1.000
2
Clinical Significance
Conservation
PhyloP100: 7.07
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 Pathogenic. Variant got 15 ACMG points.
PVS1
Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, Cryptic splice site detected, with MaxEntScore 7.7, offset of 44, new splice context is: gagGTgaga. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
PM2
Very rare variant in population databases, with high coverage;
PP3
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
PP5
Variant 16-67647603-G-T is Pathogenic according to our data. Variant chr16-67647603-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 266036.Status of the report is no_assertion_criteria_provided, 0 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CARMIL2 | NM_001013838.3 | c.871+1G>T | splice_donor_variant | ENST00000334583.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CARMIL2 | ENST00000334583.11 | c.871+1G>T | splice_donor_variant | 1 | NM_001013838.3 | A2 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152100Hom.: 0 Cov.: 32
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GnomAD4 exome AF: 6.86e-7 AC: 1AN: 1457150Hom.: 0 Cov.: 34 AF XY: 0.00000138 AC XY: 1AN XY: 724322
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GnomAD4 genome AF: 0.00000657 AC: 1AN: 152100Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74298
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:2
Revision: no assertion criteria provided
LINK: link
Submissions by phenotype
Severe combined immunodeficiency due to CARMIL2 deficiency Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Sep 28, 2018 | - - |
Combined immunodeficiency Pathogenic:1
Pathogenic, no assertion criteria provided | research | Klein lab, Ludwig-Maximilians-University | Oct 01, 2016 | Experimentally proven primary immunodeficiency; combined immunodeficiency - |
Computational scores
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Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Uncertain
D
MutationTaster
Benign
D;D
GERP RS
Splicing
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dbscSNV1_ADA
Pathogenic
dbscSNV1_RF
Pathogenic
SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_DG_spliceai
Position offset: 43
DS_DL_spliceai
Position offset: -1
Find out detailed SpliceAI scores and Pangolin per-transcript scores at