12-8604926-CAAAAAAAAA-CAAAAAAAAAAA

Variant names:

• chr12-8604926-C-CAA
• rs5796316
• NM_020661.4:c.428-6_428-5dupTT

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP6 BA1

The NM_020661.4(AICDA):​c.428-6_428-5dupTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0926 in 1,175,124 control chromosomes in the GnomAD database, including 83 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.017 (49 hom., cov: 0)
  • Exomes 𝑓: 0.10 (34 hom.)
• Consequence: AICDA NM_020661.4 splice_region, intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: 0.227

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]

ACMG classification

Verdict is Benign. Variant got -9 ACMG points.

• BP6: Variant 12-8604926-C-CAA is Benign according to our data. Variant chr12-8604926-C-CAA is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 310579.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Benign=1, Uncertain_significance=1}.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0513 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AICDA	NM_020661.4	c.428-6_428-5dupTT		splice_region_variant, intron_variant	Intron 3 of 4	ENST00000229335.11	NP_065712.1
AICDA	NM_001330343.2	c.428-36_428-35dupTT		intron_variant	Intron 3 of 4		NP_001317272.1
AICDA	NM_001410970.1	c.427+287_427+288dupTT		intron_variant	Intron 3 of 3		NP_001397899.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AICDA	ENST00000229335.11	c.428-6_428-5dupTT		splice_region_variant, intron_variant	Intron 3 of 4	1	NM_020661.4	ENSP00000229335.6

Frequencies

GnomAD3 genomes AF: 0.0172 AC: 2358 AN: 136716 Hom.: 49 Cov.: 0

Gnomad AFR AF: 0.00778

Gnomad AMI AF: 0.00224

Gnomad AMR AF: 0.0545

Gnomad ASJ AF: 0.0263

Gnomad EAS AF: 0.00228

Gnomad SAS AF: 0.0194

Gnomad FIN AF: 0.0246

Gnomad MID AF: 0.0169

Gnomad NFE AF: 0.0148

Gnomad OTH AF: 0.0151

GnomAD4 exome AF: 0.103 AC: 106472 AN: 1038412 Hom.: 34 Cov.: 34 AF XY: 0.100 AC XY: 52191 AN XY: 520326

Gnomad4 AFR exome AF: 0.0421

Gnomad4 AMR exome AF: 0.131

Gnomad4 ASJ exome AF: 0.105

Gnomad4 EAS exome AF: 0.0868

Gnomad4 SAS exome AF: 0.0733

Gnomad4 FIN exome AF: 0.0995

Gnomad4 NFE exome AF: 0.107

Gnomad4 OTH exome AF: 0.102

GnomAD4 genome AF: 0.0173 AC: 2360 AN: 136712 Hom.: 49 Cov.: 0 AF XY: 0.0183 AC XY: 1201 AN XY: 65458

Gnomad4 AFR AF: 0.00777

Gnomad4 AMR AF: 0.0545

Gnomad4 ASJ AF: 0.0263

Gnomad4 EAS AF: 0.00229

Gnomad4 SAS AF: 0.0195

Gnomad4 FIN AF: 0.0246

Gnomad4 NFE AF: 0.0148

Gnomad4 OTH AF: 0.0151

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hyperimmunoglobulin M syndrome Uncertain:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hyper-IgM syndrome type 2 Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

Sep 20, 2019

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs5796316; hg19: chr12-8757522;