chr12-8605432-T-C

Variant names:

• chr12-8605432-T-C
• rs104894984
• NM_020661.4:c.210A>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_020661.4(AICDA):​c.210A>G​(p.Leu70Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0103 in 1,614,214 control chromosomes in the GnomAD database, including 130 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0088 (10 hom., cov: 33)
  • Exomes 𝑓: 0.010 (120 hom.)
• Consequence: AICDA NM_020661.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6 O:1
• Conservation: PhyloP100: 0.586
• 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, Labcorp Genetics (formerly Invitae), Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.55).
• BP6: Variant 12-8605432-T-C is Benign according to our data. Variant chr12-8605432-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 127039.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.586 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00878 (1338/152322) while in subpopulation NFE AF = 0.0096 (653/68010). AF 95% confidence interval is 0.00899. There are 10 homozygotes in GnomAd4. There are 700 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 10 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020661.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AICDA	NM_020661.4	MANE Select	c.210A>G	p.Leu70Leu	synonymous	Exon 3 of 5	NP_065712.1	Q9GZX7-1
	AICDA	NM_001330343.2		c.210A>G	p.Leu70Leu	synonymous	Exon 3 of 5	NP_001317272.1	Q9GZX7-2
	AICDA	NM_001410970.1		c.210A>G	p.Leu70Leu	synonymous	Exon 3 of 4	NP_001397899.1	Q6QJ80

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AICDA	ENST00000229335.11	TSL:1 MANE Select	c.210A>G	p.Leu70Leu	synonymous	Exon 3 of 5	ENSP00000229335.6	Q9GZX7-1
	AICDA	ENST00000543081.6	TSL:1	c.210A>G	p.Leu70Leu	synonymous	Exon 3 of 4	ENSP00000439103.2	Q6QJ80
	AICDA	ENST00000544516.6	TSL:1	c.157-1095A>G		intron	N/A	ENSP00000439538.2	Q6QLN7

Frequencies

GnomAD3 genomes AF: 0.00880 AC: 1339 AN: 152204 Hom.: 10 Cov.: 33

Gnomad AFR AF: 0.00169

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.00360

Gnomad ASJ AF: 0.0490

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00331

Gnomad FIN AF: 0.0336

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00960

Gnomad OTH AF: 0.00669

GnomAD2 exomes AF: 0.00975 AC: 2431 AN: 249260 AF XY: 0.00961

Gnomad AFR exome AF: 0.00168

Gnomad AMR exome AF: 0.00206

Gnomad ASJ exome AF: 0.0454

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0312

Gnomad NFE exome AF: 0.00944

Gnomad OTH exome AF: 0.00842

GnomAD4 exome AF: 0.0105 AC: 15304 AN: 1461892 Hom.: 120 Cov.: 33 AF XY: 0.0103 AC XY: 7507 AN XY: 727248

African (AFR) AF: 0.00146 AC: 49 AN: 33480

American (AMR) AF: 0.00197 AC: 88 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0466 AC: 1219 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00284 AC: 245 AN: 86258

European-Finnish (FIN) AF: 0.0301 AC: 1606 AN: 53420

Middle Eastern (MID) AF: 0.00485 AC: 28 AN: 5768

European-Non Finnish (NFE) AF: 0.0103 AC: 11425 AN: 1112010

Other (OTH) AF: 0.0107 AC: 644 AN: 60396

GnomAD4 genome AF: 0.00878 AC: 1338 AN: 152322 Hom.: 10 Cov.: 33 AF XY: 0.00940 AC XY: 700 AN XY: 74492

African (AFR) AF: 0.00168 AC: 70 AN: 41586

American (AMR) AF: 0.00359 AC: 55 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0490 AC: 170 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00331 AC: 16 AN: 4830

European-Finnish (FIN) AF: 0.0336 AC: 357 AN: 10620

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.00960 AC: 653 AN: 68010

Other (OTH) AF: 0.00614 AC: 13 AN: 2116

Alfa AF: 0.0107 Hom.: 9

Bravo AF: 0.00652

Asia WGS AF: 0.00231 AC: 8 AN: 3478

EpiCase AF: 0.0105

EpiControl AF: 0.00818

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Hyper-IgM syndrome type 2 (3)
-	-	3	not provided (4)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.55
CADD	Benign	9.7
DANN	Benign	0.59
PhyloP100		0.59
Mutation Taster		=100/0	polymorphism

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: rs104894984; hg19: chr12-8758028;