12-8602350-G-A

Position:

• chr12-8602350-G-A

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 2P and 10B. PM2 BP4_Strong BP6_Moderate BS1

The NM_020661.4(AICDA):​c.*1934C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00096 in 152,162 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00096 (0 hom., cov: 32)
  • Failed GnomAD Quality Control
• Consequence: AICDA NM_020661.4 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1 O:1
• Conservation: PhyloP100: 0.189

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 -8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.94).
• BP6: Variant 12-8602350-G-A is Benign according to our data. Variant chr12-8602350-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 127036.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00096 (146/152162) while in subpopulation SAS AF= 0.00497 (24/4826). AF 95% confidence interval is 0.00343. There are 0 homozygotes in gnomad4. There are 82 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AICDA	NM_020661.4	c.*1934C>T		3_prime_UTR_variant	5/5	ENST00000229335.11	NP_065712.1
AICDA	NM_001330343.2	c.*1934C>T		3_prime_UTR_variant	5/5		NP_001317272.1
AICDA	NM_001410970.1	c.*1977C>T		3_prime_UTR_variant	4/4		NP_001397899.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AICDA	ENST00000229335.11	c.*1934C>T		3_prime_UTR_variant	5/5	1	NM_020661.4	ENSP00000229335	P1

Frequencies

GnomAD3 genomes AF: 0.000960 AC: 146 AN: 152044 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00282

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00497

Gnomad FIN AF: 0.000379

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000882

Gnomad OTH AF: 0.000956

GnomAD4 exome Data not reliable, filtered out with message: AC0 AC: 0 AN: 0 Hom.: 0 Cov.: 0 AC XY: 0 AN XY: 0

GnomAD4 genome AF: 0.000960 AC: 146 AN: 152162 Hom.: 0 Cov.: 32 AF XY: 0.00110 AC XY: 82 AN XY: 74376

Gnomad4 AFR AF: 0.000241

Gnomad4 AMR AF: 0.00281

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00497

Gnomad4 FIN AF: 0.000379

Gnomad4 NFE AF: 0.000882

Gnomad4 OTH AF: 0.000946

Alfa AF: 0.000212 Hom.: 0

Bravo AF: 0.000895

Asia WGS AF: 0.00174 AC: 6 AN: 3466

ClinVar

Significance: Likely benign

Submissions summary: Benign:1 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hyper-IgM syndrome type 2 Benign:1

Likely benign, 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 and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

not provided Other:1

not provided, no classification provided

literature only

Harris Lab, University of Minnesota

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	2.3
DANN	Benign	0.84

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: rs104894981; hg19: chr12-8754946;