rs2028373

Variant names:

• chr12-8604885-G-A
• rs2028373
• NM_020661.4:c.465C>T

Your query was ambiguous. Multiple possible variants found:

• chr12-8604885-G-A
• chr12-8604885-G-C
• chr12-8604885-G-T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_020661.4(AICDA):​c.465C>T​(p.His155His) 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:11 O:1
• Conservation: PhyloP100: -0.164
• Publications: 29 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, Ambry Genetics, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.02).
• BP6: Variant 12-8604885-G-A is Benign according to our data. Variant chr12-8604885-G-A is described in ClinVar as Benign. ClinVar VariationId is 261353.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 rank	MANE	Protein	UniProt
AICDA	NM_020661.4	c.465C>T	p.His155His	synonymous_variant	Exon 4 of 5	ENST00000229335.11	NP_065712.1
AICDA	NM_001330343.2	c.435C>T	p.His145His	synonymous_variant	Exon 4 of 5		NP_001317272.1
AICDA	NM_001410970.1	c.427+330C>T		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.465C>T	p.His155His	synonymous_variant	Exon 4 of 5	1	NM_020661.4	ENSP00000229335.6

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

GnomAD2 exomes AF: 0.597 AC: 148184 AN: 248232 AF XY: 0.598

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 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

African (AFR) AF: 0.302 AC: 10096 AN: 33396

American (AMR) AF: 0.663 AC: 29513 AN: 44502

Ashkenazi Jewish (ASJ) AF: 0.594 AC: 15497 AN: 26098

East Asian (EAS) AF: 0.469 AC: 18597 AN: 39668

South Asian (SAS) AF: 0.551 AC: 47463 AN: 86066

European-Finnish (FIN) AF: 0.610 AC: 32535 AN: 53318

Middle Eastern (MID) AF: 0.550 AC: 3135 AN: 5704

European-Non Finnish (NFE) AF: 0.648 AC: 720384 AN: 1111758

Other (OTH) AF: 0.602 AC: 36305 AN: 60330

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

African (AFR) AF: 0.319 AC: 12916 AN: 40544

American (AMR) AF: 0.626 AC: 9385 AN: 14990

Ashkenazi Jewish (ASJ) AF: 0.601 AC: 2072 AN: 3450

East Asian (EAS) AF: 0.485 AC: 2443 AN: 5034

South Asian (SAS) AF: 0.545 AC: 2577 AN: 4726

European-Finnish (FIN) AF: 0.616 AC: 5908 AN: 9592

Middle Eastern (MID) AF: 0.573 AC: 165 AN: 288

European-Non Finnish (NFE) AF: 0.646 AC: 43661 AN: 67546

Other (OTH) AF: 0.555 AC: 1139 AN: 2052

Alfa AF: 0.604 Hom.: 96971

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:11 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hyper-IgM syndrome type 2 Benign:5

Jul 14, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 10, 2014

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not specified Benign:4

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 29, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 -

Jan 24, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Sep 28, 2015

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:2 Other:1

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

GenomeConnect, ClinGen

Significance: not provided

Review Status: no classification provided

Collection Method: phenotyping only

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. -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	3.0
DANN	Benign	0.45
PhyloP100		-0.16
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2028373; hg19: chr12-8757481; COSMIC: COSV57564585;