12-8604926-CAAAAAAAAA-CAAAAAAAAAAAAA

Variant names:

• chr12-8604926-C-CAAAA
• rs5796316
• NM_020661.4:c.428-8_428-5dupTTTT

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_020661.4(AICDA):​c.428-8_428-5dupTTTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000064 in 1,249,572 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 0)
  • Exomes 𝑓: 0.0000064 (0 hom.)
• Consequence: AICDA NM_020661.4 splice_region, intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.227
• Publications: 3 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, Labcorp Genetics (formerly Invitae), Ambry Genetics

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AICDA	NM_020661.4	MANE Select	c.428-8_428-5dupTTTT		splice_region intron	N/A	NP_065712.1	Q9GZX7-1
	AICDA	NM_001330343.2		c.428-38_428-35dupTTTT		intron	N/A	NP_001317272.1	Q9GZX7-2
	AICDA	NM_001410970.1		c.427+285_427+288dupTTTT		intron	N/A	NP_001397899.1	Q6QJ80

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AICDA	ENST00000229335.11	TSL:1 MANE Select	c.428-8_428-5dupTTTT		splice_region intron	N/A	ENSP00000229335.6	Q9GZX7-1
	AICDA	ENST00000543081.6	TSL:1	c.427+285_427+288dupTTTT		intron	N/A	ENSP00000439103.2	Q6QJ80
	AICDA	ENST00000544516.6	TSL:1	c.157-593_157-590dupTTTT		intron	N/A	ENSP00000439538.2	Q6QLN7

Frequencies

GnomAD3 genomes Cov.: 0

GnomAD4 exome AF: 0.00000640 AC: 8 AN: 1249572 Hom.: 0 Cov.: 34 AF XY: 0.0000112 AC XY: 7 AN XY: 622864

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 29126

American (AMR) AF: 0.0000303 AC: 1 AN: 33044

Ashkenazi Jewish (ASJ) AF: 0.0000449 AC: 1 AN: 22248

East Asian (EAS) AF: 0.00 AC: 0 AN: 33850

South Asian (SAS) AF: 0.0000407 AC: 3 AN: 73706

European-Finnish (FIN) AF: 0.0000232 AC: 1 AN: 43092

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3618

European-Non Finnish (NFE) AF: 0.00000104 AC: 1 AN: 959052

Other (OTH) AF: 0.0000193 AC: 1 AN: 51836

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000659484), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 0

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.23

Splicing

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

Other links and lift over

dbSNP: rs5796316; hg19: chr12-8757522;