12-8605456-GAGGAAGAGC-G

Variant names:

• chr12-8605456-GAGGAAGAGC-G
• rs387906329
• NM_020661.4:c.177_185delGCTCTTCCT

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PM4 PP3 PP5

The NM_020661.4(AICDA):​c.177_185delGCTCTTCCT​(p.Leu59_Leu62delinsPhe) variant causes a disruptive inframe deletion change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (no stars). Synonymous variant affecting the same amino acid position (i.e. L59L) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: AICDA NM_020661.4 disruptive_inframe_deletion
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 8.88
• 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 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_020661.4.
• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP
• PP5: Variant 12-8605456-GAGGAAGAGC-G is Pathogenic according to our data. Variant chr12-8605456-GAGGAAGAGC-G is described in ClinVar as Pathogenic. ClinVar VariationId is 5130.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020661.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AICDA	NM_020661.4	MANE Select	c.177_185delGCTCTTCCT	p.Leu59_Leu62delinsPhe	disruptive_inframe_deletion	Exon 3 of 5	NP_065712.1
	AICDA	NM_001330343.2		c.177_185delGCTCTTCCT	p.Leu59_Leu62delinsPhe	disruptive_inframe_deletion	Exon 3 of 5	NP_001317272.1
	AICDA	NM_001410970.1		c.177_185delGCTCTTCCT	p.Leu59_Leu62delinsPhe	disruptive_inframe_deletion	Exon 3 of 4	NP_001397899.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AICDA	ENST00000229335.11	TSL:1 MANE Select	c.177_185delGCTCTTCCT	p.Leu59_Leu62delinsPhe	disruptive_inframe_deletion	Exon 3 of 5	ENSP00000229335.6
	AICDA	ENST00000543081.6	TSL:1	c.177_185delGCTCTTCCT	p.Leu59_Leu62delinsPhe	disruptive_inframe_deletion	Exon 3 of 4	ENSP00000439103.2
	AICDA	ENST00000544516.6	TSL:1	c.157-1128_157-1120delGCTCTTCCT		intron	N/A	ENSP00000439538.2

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

ClinVar submissions as Germline

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Hyper-IgM syndrome type 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		8.9
Mutation Taster		=6/194	disease causing (ClinVar)

Splicing

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

Other links and lift over

dbSNP: rs387906329; hg19: chr12-8758052;