NM_020661.4:c.585T>C

Variant names:

• chr12-8604296-A-G
• rs78590060
• NM_020661.4:c.585T>C

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_020661.4(AICDA):​c.585T>C​(p.Thr195Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000675 in 1,613,996 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0034 (1 hom., cov: 30)
  • Exomes 𝑓: 0.00040 (5 hom.)
• Consequence: AICDA NM_020661.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.394
• 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.017).
• BP6: Variant 12-8604296-A-G is Benign according to our data. Variant chr12-8604296-A-G is described in ClinVar as Benign. ClinVar VariationId is 496448.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.394 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00336 (512/152262) while in subpopulation AFR AF = 0.0109 (453/41546). AF 95% confidence interval is 0.0101. There are 1 homozygotes in GnomAd4. There are 246 alleles in the male GnomAd4 subpopulation. Median coverage is 30. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 5 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.585T>C	p.Thr195Thr	synonymous	Exon 5 of 5	NP_065712.1	Q9GZX7-1
	AICDA	NM_001330343.2		c.555T>C	p.Thr185Thr	synonymous	Exon 5 of 5	NP_001317272.1	Q9GZX7-2
	AICDA	NM_001410970.1		c.*31T>C		3_prime_UTR	Exon 4 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.585T>C	p.Thr195Thr	synonymous	Exon 5 of 5	ENSP00000229335.6	Q9GZX7-1
	AICDA	ENST00000544516.6	TSL:1	c.198T>C	p.Thr66Thr	synonymous	Exon 3 of 3	ENSP00000439538.2	Q6QLN7
	AICDA	ENST00000543081.6	TSL:1	c.*31T>C		3_prime_UTR	Exon 4 of 4	ENSP00000439103.2	Q6QJ80

Frequencies

GnomAD3 genomes AF: 0.00335 AC: 509 AN: 152144 Hom.: 1 Cov.: 30

Gnomad AFR AF: 0.0109

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00341

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.000978 AC: 244 AN: 249552 AF XY: 0.000694

Gnomad AFR exome AF: 0.0130

Gnomad AMR exome AF: 0.00107

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000556

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000177

Gnomad OTH exome AF: 0.000495

GnomAD4 exome AF: 0.000395 AC: 578 AN: 1461734 Hom.: 5 Cov.: 31 AF XY: 0.000349 AC XY: 254 AN XY: 727178

African (AFR) AF: 0.0132 AC: 443 AN: 33466

American (AMR) AF: 0.00123 AC: 55 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53412

Middle Eastern (MID) AF: 0.00173 AC: 10 AN: 5768

European-Non Finnish (NFE) AF: 0.0000162 AC: 18 AN: 1111890

Other (OTH) AF: 0.000845 AC: 51 AN: 60390

GnomAD4 genome AF: 0.00336 AC: 512 AN: 152262 Hom.: 1 Cov.: 30 AF XY: 0.00330 AC XY: 246 AN XY: 74462

African (AFR) AF: 0.0109 AC: 453 AN: 41546

American (AMR) AF: 0.00340 AC: 52 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68016

Other (OTH) AF: 0.00237 AC: 5 AN: 2112

Alfa AF: 0.00167 Hom.: 1

Bravo AF: 0.00379

Asia WGS AF: 0.00202 AC: 7 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Hyper-IgM syndrome type 2 (2)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	5.4
DANN	Benign	0.59
PhyloP100		-0.39
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: rs78590060; hg19: chr12-8756892;