rs104894984

Positions:

• chr12-8605432-T-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_020661.4(AICDA):​c.210A>G​(p.Leu70=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0103 in 1,614,214 control chromosomes in the GnomAD database, including 130 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0088 (10 hom., cov: 33)
  • Exomes 𝑓: 0.010 (120 hom.)
• Consequence: AICDA NM_020661.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5 O:1
• Conservation: PhyloP100: 0.586

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.55).
• BP6: Variant 12-8605432-T-C is Benign according to our data. Variant chr12-8605432-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 127039.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.586 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00878 (1338/152322) while in subpopulation NFE AF= 0.0096 (653/68010). AF 95% confidence interval is 0.00899. There are 10 homozygotes in gnomad4. There are 700 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 10 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AICDA	NM_020661.4	c.210A>G	p.Leu70=	synonymous_variant	3/5	ENST00000229335.11
AICDA	NM_001330343.2	c.210A>G	p.Leu70=	synonymous_variant	3/5
AICDA	NM_001410970.1	c.210A>G	p.Leu70=	synonymous_variant	3/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AICDA	ENST00000229335.11	c.210A>G	p.Leu70=	synonymous_variant	3/5	1	NM_020661.4	P1

Frequencies

GnomAD3 genomes AF: 0.00880 AC: 1339 AN: 152204 Hom.: 10 Cov.: 33

Gnomad AFR AF: 0.00169

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.00360

Gnomad ASJ AF: 0.0490

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00331

Gnomad FIN AF: 0.0336

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00960

Gnomad OTH AF: 0.00669

GnomAD3 exomes AF: 0.00975 AC: 2431 AN: 249260 Hom.: 26 AF XY: 0.00961 AC XY: 1300 AN XY: 135274

Gnomad AFR exome AF: 0.00168

Gnomad AMR exome AF: 0.00206

Gnomad ASJ exome AF: 0.0454

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00288

Gnomad FIN exome AF: 0.0312

Gnomad NFE exome AF: 0.00944

Gnomad OTH exome AF: 0.00842

GnomAD4 exome AF: 0.0105 AC: 15304 AN: 1461892 Hom.: 120 Cov.: 33 AF XY: 0.0103 AC XY: 7507 AN XY: 727248

Gnomad4 AFR exome AF: 0.00146

Gnomad4 AMR exome AF: 0.00197

Gnomad4 ASJ exome AF: 0.0466

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00284

Gnomad4 FIN exome AF: 0.0301

Gnomad4 NFE exome AF: 0.0103

Gnomad4 OTH exome AF: 0.0107

GnomAD4 genome AF: 0.00878 AC: 1338 AN: 152322 Hom.: 10 Cov.: 33 AF XY: 0.00940 AC XY: 700 AN XY: 74492

Gnomad4 AFR AF: 0.00168

Gnomad4 AMR AF: 0.00359

Gnomad4 ASJ AF: 0.0490

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00331

Gnomad4 FIN AF: 0.0336

Gnomad4 NFE AF: 0.00960

Gnomad4 OTH AF: 0.00614

Alfa AF: 0.0107 Hom.: 9

Bravo AF: 0.00652

Asia WGS AF: 0.00231 AC: 8 AN: 3478

EpiCase AF: 0.0105

EpiControl AF: 0.00818

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hyper-IgM syndrome type 2 Benign:3

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Apr 06, 2022	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

not provided Benign:2 Other:1

not provided, no classification provided	literature only	Harris Lab, University of Minnesota	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2024	AICDA: BP4, BP7, BS2 -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 09, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.55
CADD	Benign	9.7
DANN	Benign	0.59

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs104894984; hg19: chr12-8758028;