12-8604885-G-A

Position:

• chr12-8604885-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_020661.4(AICDA):​c.465C>T​(p.His155=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.618 in 1,609,966 control chromosomes in the GnomAD database, including 312,561 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.54 (23255 hom., cov: 26)
  • Exomes 𝑓: 0.63 (289306 hom.)
• Consequence: AICDA NM_020661.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10 O:1
• Conservation: PhyloP100: -0.164

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=-0.82).
• BP6: Variant 12-8604885-G-A is Benign according to our data. Variant chr12-8604885-G-A is described in ClinVar as [Benign]. Clinvar id is 261353.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-8604885-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.164 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.641 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AICDA	NM_020661.4	c.465C>T	p.His155=	synonymous_variant	4/5	ENST00000229335.11
AICDA	NM_001330343.2	c.435C>T	p.His145=	synonymous_variant	4/5
AICDA	NM_001410970.1	c.427+330C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AICDA	ENST00000229335.11	c.465C>T	p.His155=	synonymous_variant	4/5	1	NM_020661.4	P1

Frequencies

GnomAD3 genomes AF: 0.542 AC: 80823 AN: 149028 Hom.: 23245 Cov.: 26

Gnomad AFR AF: 0.319

Gnomad AMI AF: 0.649

Gnomad AMR AF: 0.626

Gnomad ASJ AF: 0.601

Gnomad EAS AF: 0.484

Gnomad SAS AF: 0.544

Gnomad FIN AF: 0.616

Gnomad MID AF: 0.561

Gnomad NFE AF: 0.646

Gnomad OTH AF: 0.557

GnomAD3 exomes AF: 0.597 AC: 148184 AN: 248232 Hom.: 45374 AF XY: 0.598 AC XY: 80672 AN XY: 134922

Gnomad AFR exome AF: 0.312

Gnomad AMR exome AF: 0.665

Gnomad ASJ exome AF: 0.601

Gnomad EAS exome AF: 0.503

Gnomad SAS exome AF: 0.542

Gnomad FIN exome AF: 0.611

Gnomad NFE exome AF: 0.641

Gnomad OTH exome AF: 0.604

GnomAD4 exome AF: 0.625 AC: 913525 AN: 1460840 Hom.: 289306 Cov.: 66 AF XY: 0.625 AC XY: 453963 AN XY: 726714

Gnomad4 AFR exome AF: 0.302

Gnomad4 AMR exome AF: 0.663

Gnomad4 ASJ exome AF: 0.594

Gnomad4 EAS exome AF: 0.469

Gnomad4 SAS exome AF: 0.551

Gnomad4 FIN exome AF: 0.610

Gnomad4 NFE exome AF: 0.648

Gnomad4 OTH exome AF: 0.602

GnomAD4 genome AF: 0.542 AC: 80853 AN: 149126 Hom.: 23255 Cov.: 26 AF XY: 0.543 AC XY: 39353 AN XY: 72528

Gnomad4 AFR AF: 0.319

Gnomad4 AMR AF: 0.626

Gnomad4 ASJ AF: 0.601

Gnomad4 EAS AF: 0.485

Gnomad4 SAS AF: 0.545

Gnomad4 FIN AF: 0.616

Gnomad4 NFE AF: 0.646

Gnomad4 OTH AF: 0.555

Alfa AF: 0.618 Hom.: 71819

Bravo AF: 0.533

Asia WGS AF: 0.457 AC: 1590 AN: 3476

EpiCase AF: 0.644

EpiControl AF: 0.639

ClinVar

Significance: Benign

Submissions summary: Benign:10 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hyper-IgM syndrome type 2 Benign:5

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
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	Genome Diagnostics Laboratory, University Medical Center Utrecht	Oct 10, 2014	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 14, 2021	- -

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan	Jan 24, 2024	This variant is classified as Benign based on local population frequency. This variant was detected in 86% of patients studied by a panel of primary immunodeficiencies. Number of patients: 82. Only high quality variants are reported. -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 29, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 28, 2015	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided Benign:1 Other:1

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
not provided, no classification provided	phenotyping only	GenomeConnect, ClinGen	-	Variant interpreted as Benign and reported on 04-27-2020 by Lab or GTR ID 500031. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. This variant was reported in an individual referred for clinical diagnostic genetic testing. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	3.0
DANN	Benign	0.45

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs2028373; hg19: chr12-8757481; COSMIC: COSV57564585;