12-8604926-CAAAAAAAAA-CAAAAAAAAAAAA

Variant names:

• chr12-8604926-C-CAAA
• rs5796316
• NM_020661.4:c.428-7_428-5dupTTT

Variant summary

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

The NM_020661.4(AICDA):​c.428-7_428-5dupTTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000317 in 1,383,320 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: 𝑓 0.000080 (0 hom., cov: 0)
  • Exomes 𝑓: 0.00034 (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.428-7_428-5dupTTT		splice_region intron	N/A	NP_065712.1	Q9GZX7-1
	AICDA	NM_001330343.2		c.428-37_428-35dupTTT		intron	N/A	NP_001317272.1	Q9GZX7-2
	AICDA	NM_001410970.1		c.427+286_427+288dupTTT		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.428-7_428-5dupTTT		splice_region intron	N/A	ENSP00000229335.6	Q9GZX7-1
	AICDA	ENST00000543081.6	TSL:1	c.427+286_427+288dupTTT		intron	N/A	ENSP00000439103.2	Q6QJ80
	AICDA	ENST00000544516.6	TSL:1	c.157-592_157-590dupTTT		intron	N/A	ENSP00000439538.2	Q6QLN7

Frequencies

GnomAD3 genomes AF: 0.0000804 AC: 11 AN: 136810 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.0000274

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000734

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00208

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00129 AC: 190 AN: 147494 AF XY: 0.00131

Gnomad AFR exome AF: 0.000446

Gnomad AMR exome AF: 0.00253

Gnomad ASJ exome AF: 0.000751

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00167

Gnomad NFE exome AF: 0.000835

Gnomad OTH exome AF: 0.00132

GnomAD4 exome AF: 0.000343 AC: 428 AN: 1246514 Hom.: 0 Cov.: 34 AF XY: 0.000391 AC XY: 243 AN XY: 621404

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

African (AFR) AF: 0.000172 AC: 5 AN: 29102

American (AMR) AF: 0.00258 AC: 85 AN: 32946

Ashkenazi Jewish (ASJ) AF: 0.000361 AC: 8 AN: 22186

East Asian (EAS) AF: 0.0000889 AC: 3 AN: 33742

South Asian (SAS) AF: 0.00171 AC: 126 AN: 73526

European-Finnish (FIN) AF: 0.000768 AC: 33 AN: 42952

Middle Eastern (MID) AF: 0.000554 AC: 2 AN: 3610

European-Non Finnish (NFE) AF: 0.000146 AC: 140 AN: 956750

Other (OTH) AF: 0.000503 AC: 26 AN: 51700

⚠️ 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: 0.0000804 AC: 11 AN: 136806 Hom.: 0 Cov.: 0 AF XY: 0.000122 AC XY: 8 AN XY: 65510

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

African (AFR) AF: 0.0000273 AC: 1 AN: 36570

American (AMR) AF: 0.0000733 AC: 1 AN: 13644

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3350

East Asian (EAS) AF: 0.00 AC: 0 AN: 4812

South Asian (SAS) AF: 0.00209 AC: 9 AN: 4298

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6584

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 272

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 64524

Other (OTH) AF: 0.00 AC: 0 AN: 1860

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.0000768129), which strongly suggests a high chance of mosaicism in these individuals.

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
Mutation Taster		=100/0	polymorphism

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;