12-8605211-G-A
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Variant summary
Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PM2BP4_StrongBP6BS1
The NM_020661.4(AICDA):c.427+4C>T variant causes a splice donor region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000256 in 1,613,750 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.0012 ( 0 hom., cov: 33)
Exomes 𝑓: 0.00016 ( 0 hom. )
Consequence
AICDA
NM_020661.4 splice_donor_region, intron
NM_020661.4 splice_donor_region, intron
Scores
2
Splicing: ADA: 0.001280
2
Clinical Significance
Conservation
PhyloP100: -0.974
Genes affected
AICDA (HGNC:13203): (activation induced cytidine deaminase) This gene encodes a RNA-editing deaminase that is a member of the cytidine deaminase family. AICDA is specifically expressed and active in germinal center-like B cells. In the germinal center, AICDA is involved in somatic hypermutation, gene conversion, and class-switch recombination of immunoglobulin genes. An epigenetic role in neoplastic transformation and lymphoma progression has been experimentally ascribed to AICDA using mouse models. Defects in this gene are the cause of autosomal recessive hyper-IgM immunodeficiency syndrome type 2 (HIGM2). [provided by RefSeq, Jul 2020]
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ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -7 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.83).
BP6
Variant 12-8605211-G-A is Benign according to our data. Variant chr12-8605211-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 310580.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=1}.
BS1
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0012 (183/152318) while in subpopulation AFR AF= 0.00414 (172/41562). AF 95% confidence interval is 0.00363. There are 0 homozygotes in gnomad4. There are 75 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
|---|---|---|---|---|---|---|---|
| AICDA | NM_020661.4 | c.427+4C>T | splice_donor_region_variant, intron_variant | ENST00000229335.11 | |||
| AICDA | NM_001330343.2 | c.427+4C>T | splice_donor_region_variant, intron_variant | ||||
| AICDA | NM_001410970.1 | c.427+4C>T | splice_donor_region_variant, intron_variant |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| AICDA | ENST00000229335.11 | c.427+4C>T | splice_donor_region_variant, intron_variant | 1 | NM_020661.4 | P1 |
Frequencies
GnomAD3 genomes 0.00120 AC: 183AN: 152200Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.000373 AC: 92AN: 246520Hom.: 0 AF XY: 0.000298 AC XY: 40AN XY: 134298
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GnomAD4 exome AF: 0.000157 AC: 230AN: 1461432Hom.: 0 Cov.: 33 AF XY: 0.000144 AC XY: 105AN XY: 727026
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GnomAD4 genome 0.00120 AC: 183AN: 152318Hom.: 0 Cov.: 33 AF XY: 0.00101 AC XY: 75AN XY: 74478
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:2
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Hyper-IgM syndrome type 2 Uncertain:1Benign:2
| Uncertain significance, criteria provided, single submitter | clinical testing | New York Genome Center | Mar 04, 2021 | - - |
| Likely benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 14, 2024 | - - |
| Likely benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 13, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. - |
Computational scores
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Name
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Splicing
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dbscSNV1_ADA
Benign
dbscSNV1_RF
Benign
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at