rs387906328

Variant names:

• chr12-8606980-TGGTAAAGAAACTTCCTCCG-T
• rs387906328
• NM_020661.4:c.22_40delCGGAGGAAGTTTCTTTACC

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PVS1 PP5

The NM_020661.4(AICDA):​c.22_40delCGGAGGAAGTTTCTTTACC​(p.Arg8AsnfsTer19) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Pathogenic (no stars). Synonymous variant affecting the same amino acid position (i.e. R8R) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: AICDA NM_020661.4 frameshift
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 8.90
• Publications: 1 publications found

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]

AICDA Gene-Disease associations (from GenCC):

• hyper-IgM syndrome type 2

  Inheritance: AD, AR Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Ambry Genetics, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Likely_pathogenic. The variant received 9 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 29 pathogenic variants in the truncated region.
• PP5: Variant 12-8606980-TGGTAAAGAAACTTCCTCCG-T is Pathogenic according to our data. Variant chr12-8606980-TGGTAAAGAAACTTCCTCCG-T is described in ClinVar as [Pathogenic]. Clinvar id is 5129.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AICDA	NM_020661.4	c.22_40delCGGAGGAAGTTTCTTTACC	p.Arg8AsnfsTer19	frameshift_variant	Exon 2 of 5	ENST00000229335.11	NP_065712.1
AICDA	NM_001330343.2	c.22_40delCGGAGGAAGTTTCTTTACC	p.Arg8AsnfsTer19	frameshift_variant	Exon 2 of 5		NP_001317272.1
AICDA	NM_001410970.1	c.22_40delCGGAGGAAGTTTCTTTACC	p.Arg8AsnfsTer19	frameshift_variant	Exon 2 of 4		NP_001397899.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AICDA	ENST00000229335.11	c.22_40delCGGAGGAAGTTTCTTTACC	p.Arg8AsnfsTer19	frameshift_variant	Exon 2 of 5	1	NM_020661.4	ENSP00000229335.6

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Hyper-IgM syndrome type 2 Pathogenic:1

Sep 01, 2000

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		8.9
Mutation Taster		=3/197	disease causing (ClinVar)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs387906328; hg19: chr12-8759576;