12-8604885-G-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BA1

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

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:11O:1

Conservation

PhyloP100: -0.164

Publications

29 publications found

Variant links:

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)

AICDA links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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 link	c.465C>T	p.His155His	synonymous_variant	Exon 4 of 5	ENST00000229335.11	NP_065712.1	Q9GZX7-1Q546Y9Q7Z599
AICDA	NM_001330343.2 link	c.435C>T	p.His145His	synonymous_variant	Exon 4 of 5		NP_001317272.1	Q9GZX7-2Q7Z599
AICDA	NM_001410970.1 link	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 link	c.465C>T	p.His155His	synonymous_variant	Exon 4 of 5	1	NM_020661.4	ENSP00000229335.6		Q9GZX7-1

Frequencies

GnomAD3 genomes

AF:

0.542

AC:

80823

AN:

149028

Hom.:

23245

Cov.:

show subpopulations

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

show subpopulations

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.:

AF XY:

0.625

AC XY:

453963

AN XY:

726714

show subpopulations

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

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.466

Heterozygous variant carriers

20187

40373

60560

80746

100933

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

18778

37556

56334

75112

93890

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.542

AC:

80853

AN:

149126

Hom.:

23255

Cov.:

AF XY:

0.543

AC XY:

39353

AN XY:

72528

show subpopulations

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

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1645

3289

4934

6578

8223

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

700

1400

2100

2800

3500

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

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:11Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

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:2Other: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

(source)

DANN

Benign

0.45

PhyloP100

-0.16

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over