12-8604926-CAAAAAAAA-CAAAAAAAAA

Position:

• chr12-8604926-CAAAAAAAA-CAAAAAAAAA

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_020661.4(AICDA):​c.428-5_428-4insT variant causes a splice region, splice polypyrimidine tract, 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, splice_polypyrimidine_tract, intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6 O:1
• Conservation: PhyloP100: 0.227

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 -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 id 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/exons	MANE	UniProt
AICDA	NM_020661.4	c.428-5_428-4insT		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000229335.11
AICDA	NM_001330343.2	c.428-35_428-34insT		intron_variant
AICDA	NM_001410970.1	c.427+288_427+289insT		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AICDA	ENST00000229335.11	c.428-5_428-4insT		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_020661.4	P1

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

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

Gnomad4 AFR exome AF: 0.469

Gnomad4 AMR exome AF: 0.494

Gnomad4 ASJ exome AF: 0.509

Gnomad4 EAS exome AF: 0.518

Gnomad4 SAS exome AF: 0.508

Gnomad4 FIN exome AF: 0.536

Gnomad4 NFE exome AF: 0.519

Gnomad4 OTH exome AF: 0.515

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

Gnomad4 AFR AF: 0.691

Gnomad4 AMR AF: 0.871

Gnomad4 ASJ AF: 0.942

Gnomad4 EAS AF: 0.944

Gnomad4 SAS AF: 0.938

Gnomad4 FIN AF: 0.941

Gnomad4 NFE AF: 0.965

Gnomad4 OTH AF: 0.884

ClinVar

Significance: Benign

Submissions summary: Benign:6 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

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 99% of patients studied by a panel of primary immunodeficiencies. Number of patients: 94. 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 -

Hyper-IgM syndrome type 2 Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 14, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

not provided Benign:1 Other:1

Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 09, 2018	- -
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. -

Hyperimmunoglobulin M syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

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: rs5796316; hg19: chr12-8757522;