12-8604926-C-CA

Variant names:

• chr12-8604926-C-CA
• rs5796316
• NM_020661.4:c.428-5dupT

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_020661.4(AICDA):​c.428-5dupT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.88 (53347 hom., cov: 0)
  • Exomes 𝑓: 0.52 (25645 hom.)
  • Failed GnomAD Quality Control
• Consequence: AICDA NM_020661.4 splice_region, intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7 O:1
• 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, Ambry Genetics, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -16 ACMG points.

• BP6: Variant 12-8604926-C-CA is Benign according to our data. Variant chr12-8604926-C-CA is described in ClinVar as Benign. ClinVar VariationId is 310578.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.958 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AICDA	NM_020661.4	c.428-5dupT		splice_region_variant, intron_variant	Intron 3 of 4	ENST00000229335.11	NP_065712.1
AICDA	NM_001330343.2	c.428-35dupT		intron_variant	Intron 3 of 4		NP_001317272.1
AICDA	NM_001410970.1	c.427+288dupT		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.428-5dupT		splice_region_variant, intron_variant	Intron 3 of 4	1	NM_020661.4	ENSP00000229335.6

Frequencies

GnomAD3 genomes AF: 0.878 AC: 120071 AN: 136786 Hom.: 53358 Cov.: 0

Gnomad AFR AF: 0.691

Gnomad AMI AF: 0.959

Gnomad AMR AF: 0.871

Gnomad ASJ AF: 0.942

Gnomad EAS AF: 0.944

Gnomad SAS AF: 0.938

Gnomad FIN AF: 0.941

Gnomad MID AF: 0.899

Gnomad NFE AF: 0.965

Gnomad OTH AF: 0.884

GnomAD2 exomes AF: 0.530 AC: 78155 AN: 147494 AF XY: 0.529

Gnomad AFR exome AF: 0.462

Gnomad AMR exome AF: 0.500

Gnomad ASJ exome AF: 0.507

Gnomad EAS exome AF: 0.535

Gnomad FIN exome AF: 0.583

Gnomad NFE exome AF: 0.544

Gnomad OTH exome AF: 0.521

GnomAD4 exome Data not reliable, filtered out with message: InbreedingCoeff AF: 0.517 AC: 645038 AN: 1247476 Hom.: 25645 Cov.: 34 AF XY: 0.517 AC XY: 321303 AN XY: 621834

African (AFR) AF: 0.469 AC: 13207 AN: 28144

American (AMR) AF: 0.494 AC: 16215 AN: 32802

Ashkenazi Jewish (ASJ) AF: 0.509 AC: 11303 AN: 22218

East Asian (EAS) AF: 0.518 AC: 17501 AN: 33762

South Asian (SAS) AF: 0.508 AC: 37396 AN: 73544

European-Finnish (FIN) AF: 0.536 AC: 23059 AN: 43006

Middle Eastern (MID) AF: 0.512 AC: 1846 AN: 3606

European-Non Finnish (NFE) AF: 0.519 AC: 497865 AN: 958674

Other (OTH) AF: 0.515 AC: 26646 AN: 51720

GnomAD4 genome AF: 0.878 AC: 120054 AN: 136782 Hom.: 53347 Cov.: 0 AF XY: 0.876 AC XY: 57375 AN XY: 65492

African (AFR) AF: 0.691 AC: 25202 AN: 36496

American (AMR) AF: 0.871 AC: 11890 AN: 13644

Ashkenazi Jewish (ASJ) AF: 0.942 AC: 3160 AN: 3354

East Asian (EAS) AF: 0.944 AC: 4541 AN: 4812

South Asian (SAS) AF: 0.938 AC: 4029 AN: 4294

European-Finnish (FIN) AF: 0.941 AC: 6199 AN: 6590

Middle Eastern (MID) AF: 0.901 AC: 245 AN: 272

European-Non Finnish (NFE) AF: 0.965 AC: 62286 AN: 64566

Other (OTH) AF: 0.884 AC: 1645 AN: 1860

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Benign

Submissions summary: Benign:7 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Feb 16, 2025

Laboratory of Genetics, Children's Clinical University Hospital Latvia

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 99% of patients studied by a panel of primary immunodeficiencies. Number of patients: 94. Only high quality variants are reported. -

Hyper-IgM syndrome type 2 Benign:2

Jul 14, 2021

Genome-Nilou Lab

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

- -

not provided Benign:1 Other:1

Aug 09, 2018

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. -

Hyperimmunoglobulin M syndrome Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.23
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs5796316; hg19: chr12-8757522;