chr12-8606973-T-C

Position:

• chr12-8606973-T-C

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6 BP7

The NM_020661.4(AICDA):​c.48A>G​(p.Lys16Lys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00126 in 1,614,140 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0011 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0013 (0 hom.)
• Consequence: AICDA NM_020661.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:3
• Conservation: PhyloP100: 2.41

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 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.63).
• BP6: Variant 12-8606973-T-C is Benign according to our data. Variant chr12-8606973-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 282568.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=2, Benign=1}.
• BP7: Synonymous conserved (PhyloP=2.41 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AICDA	NM_020661.4	c.48A>G	p.Lys16Lys	synonymous_variant	2/5	ENST00000229335.11	NP_065712.1
AICDA	NM_001330343.2	c.48A>G	p.Lys16Lys	synonymous_variant	2/5		NP_001317272.1
AICDA	NM_001410970.1	c.48A>G	p.Lys16Lys	synonymous_variant	2/4		NP_001397899.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AICDA	ENST00000229335.11	c.48A>G	p.Lys16Lys	synonymous_variant	2/5	1	NM_020661.4	ENSP00000229335.6

Frequencies

GnomAD3 genomes AF: 0.00115 AC: 175 AN: 152160 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000362

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00288

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000660

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00144

Gnomad OTH AF: 0.00526

GnomAD3 exomes AF: 0.00117 AC: 291 AN: 249484 Hom.: 0 AF XY: 0.00104 AC XY: 141 AN XY: 135354

Gnomad AFR exome AF: 0.000452

Gnomad AMR exome AF: 0.00229

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000981

Gnomad FIN exome AF: 0.000510

Gnomad NFE exome AF: 0.00155

Gnomad OTH exome AF: 0.00264

GnomAD4 exome AF: 0.00127 AC: 1853 AN: 1461862 Hom.: 0 Cov.: 33 AF XY: 0.00122 AC XY: 885 AN XY: 727230

Gnomad4 AFR exome AF: 0.000478

Gnomad4 AMR exome AF: 0.00233

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.000562

Gnomad4 NFE exome AF: 0.00145

Gnomad4 OTH exome AF: 0.00139

GnomAD4 genome AF: 0.00115 AC: 175 AN: 152278 Hom.: 1 Cov.: 32 AF XY: 0.00106 AC XY: 79 AN XY: 74472

Gnomad4 AFR AF: 0.000361

Gnomad4 AMR AF: 0.00288

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000660

Gnomad4 NFE AF: 0.00144

Gnomad4 OTH AF: 0.00520

Alfa AF: 0.000945 Hom.: 0

Bravo AF: 0.00122

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00153

EpiControl AF: 0.00202

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hyper-IgM syndrome type 2 Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 18, 2024	- -

not provided Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2024	AICDA: BP4, BP7 -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 22, 2018	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Jun 18, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.63
CADD	Benign	8.6
DANN	Benign	0.53

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: rs186739900; hg19: chr12-8759569;