12-8606849-C-T

Position:

• chr12-8606849-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_020661.4(AICDA):​c.156+16G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.49 in 1,613,040 control chromosomes in the GnomAD database, including 201,129 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.56 (25191 hom., cov: 32)
  • Exomes 𝑓: 0.48 (175938 hom.)
• Consequence: AICDA NM_020661.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.291

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 12-8606849-C-T is Benign according to our data. Variant chr12-8606849-C-T is described in ClinVar as [Benign]. Clinvar id is 261352.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-8606849-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.79 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AICDA	NM_020661.4	c.156+16G>A		intron_variant		ENST00000229335.11
AICDA	NM_001330343.2	c.156+16G>A		intron_variant
AICDA	NM_001410970.1	c.156+16G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AICDA	ENST00000229335.11	c.156+16G>A		intron_variant		1	NM_020661.4	P1

Frequencies

GnomAD3 genomes AF: 0.559 AC: 84882 AN: 151946 Hom.: 25146 Cov.: 32

Gnomad AFR AF: 0.740

Gnomad AMI AF: 0.499

Gnomad AMR AF: 0.497

Gnomad ASJ AF: 0.380

Gnomad EAS AF: 0.810

Gnomad SAS AF: 0.588

Gnomad FIN AF: 0.563

Gnomad MID AF: 0.389

Gnomad NFE AF: 0.453

Gnomad OTH AF: 0.494

GnomAD3 exomes AF: 0.526 AC: 130961 AN: 249030 Hom.: 36054 AF XY: 0.518 AC XY: 70066 AN XY: 135132

Gnomad AFR exome AF: 0.744

Gnomad AMR exome AF: 0.509

Gnomad ASJ exome AF: 0.375

Gnomad EAS exome AF: 0.793

Gnomad SAS exome AF: 0.565

Gnomad FIN exome AF: 0.573

Gnomad NFE exome AF: 0.455

Gnomad OTH exome AF: 0.475

GnomAD4 exome AF: 0.483 AC: 704926 AN: 1460976 Hom.: 175938 Cov.: 43 AF XY: 0.483 AC XY: 351096 AN XY: 726854

Gnomad4 AFR exome AF: 0.745

Gnomad4 AMR exome AF: 0.506

Gnomad4 ASJ exome AF: 0.382

Gnomad4 EAS exome AF: 0.838

Gnomad4 SAS exome AF: 0.564

Gnomad4 FIN exome AF: 0.567

Gnomad4 NFE exome AF: 0.453

Gnomad4 OTH exome AF: 0.492

GnomAD4 genome AF: 0.559 AC: 84987 AN: 152064 Hom.: 25191 Cov.: 32 AF XY: 0.566 AC XY: 42087 AN XY: 74308

Gnomad4 AFR AF: 0.739

Gnomad4 AMR AF: 0.497

Gnomad4 ASJ AF: 0.380

Gnomad4 EAS AF: 0.811

Gnomad4 SAS AF: 0.588

Gnomad4 FIN AF: 0.563

Gnomad4 NFE AF: 0.453

Gnomad4 OTH AF: 0.500

Alfa AF: 0.494 Hom.: 6167

Bravo AF: 0.559

Asia WGS AF: 0.681 AC: 2364 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hyper-IgM syndrome type 2 Benign:4

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 14, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Oct 09, 2014	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
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 66% of patients studied by a panel of primary immunodeficiencies. Number of patients: 63. 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 -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 03, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.69
DANN	Benign	0.56

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: rs2518144; hg19: chr12-8759445; COSMIC: COSV57565902;