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. The variant received -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
• 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: Benign. The variant received -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 VariationId is 310579.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0513 is higher than 0.05.

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.428-6_428-5dupTT		splice_region intron	N/A	NP_065712.1	Q9GZX7-1
	AICDA	NM_001330343.2		c.428-36_428-35dupTT		intron	N/A	NP_001317272.1	Q9GZX7-2
	AICDA	NM_001410970.1		c.427+287_427+288dupTT		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.428-6_428-5dupTT		splice_region intron	N/A	ENSP00000229335.6	Q9GZX7-1
	AICDA	ENST00000543081.6	TSL:1	c.427+287_427+288dupTT		intron	N/A	ENSP00000439103.2	Q6QJ80
	AICDA	ENST00000544516.6	TSL:1	c.157-591_157-590dupTT		intron	N/A	ENSP00000439538.2	Q6QLN7

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

GnomAD2 exomes AF: 0.0626 AC: 9227 AN: 147494 AF XY: 0.0607

Gnomad AFR exome AF: 0.0253

Gnomad AMR exome AF: 0.121

Gnomad ASJ exome AF: 0.0699

Gnomad EAS exome AF: 0.0438

Gnomad FIN exome AF: 0.0702

Gnomad NFE exome AF: 0.0517

Gnomad OTH exome AF: 0.0618

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

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

African (AFR) AF: 0.0421 AC: 1143 AN: 27130

American (AMR) AF: 0.131 AC: 4062 AN: 31078

Ashkenazi Jewish (ASJ) AF: 0.105 AC: 2052 AN: 19580

East Asian (EAS) AF: 0.0868 AC: 2615 AN: 30116

South Asian (SAS) AF: 0.0733 AC: 4838 AN: 66028

European-Finnish (FIN) AF: 0.0995 AC: 3908 AN: 39282

Middle Eastern (MID) AF: 0.100 AC: 319 AN: 3180

European-Non Finnish (NFE) AF: 0.107 AC: 83041 AN: 777910

Other (OTH) AF: 0.102 AC: 4494 AN: 44108

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

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

African (AFR) AF: 0.00777 AC: 284 AN: 36554

American (AMR) AF: 0.0545 AC: 743 AN: 13622

Ashkenazi Jewish (ASJ) AF: 0.0263 AC: 88 AN: 3350

East Asian (EAS) AF: 0.00229 AC: 11 AN: 4806

South Asian (SAS) AF: 0.0195 AC: 84 AN: 4298

European-Finnish (FIN) AF: 0.0246 AC: 162 AN: 6574

Middle Eastern (MID) AF: 0.0184 AC: 5 AN: 272

European-Non Finnish (NFE) AF: 0.0148 AC: 953 AN: 64484

Other (OTH) AF: 0.0151 AC: 28 AN: 1860

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	1	Hyper-IgM syndrome type 2 (1)
-	1	-	Hyperimmunoglobulin M syndrome (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.23
Mutation Taster		=100/0	polymorphism (auto)

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;