Genetic Variant AICDA:p.His155Gln (chr12-8604885-G-C) – ACMG Classification: Likely_benign (-1 pts)

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 3P and 4B. PM2PP2BP4_Strong

The NM_020661.4(AICDA):c.465C>G(p.His155Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,038 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H155R) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 26)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

AICDA
NM_020661.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.164

Publications

29 publications found

Variant links:

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, Ambry Genetics, Labcorp Genetics (formerly Invitae)

AICDA links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 13 curated pathogenic missense variants (we use a threshold of 10). The gene has 2 curated benign missense variants. Gene score misZ: 1.3381 (below the threshold of 3.09). Trascript score misZ: 0.98605 (below the threshold of 3.09). GenCC associations: The gene is linked to hyper-IgM syndrome type 2.

BP4

Computational evidence support a benign effect (MetaRNN=0.03096351).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AICDA	NM_020661.4 link	c.465C>G	p.His155Gln	missense_variant	Exon 4 of 5	ENST00000229335.11	NP_065712.1	Q9GZX7-1Q546Y9Q7Z599
AICDA	NM_001330343.2 link	c.435C>G	p.His145Gln	missense_variant	Exon 4 of 5		NP_001317272.1	Q9GZX7-2Q7Z599
AICDA	NM_001410970.1 link	c.427+330C>G		intron_variant	Intron 3 of 3		NP_001397899.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AICDA	ENST00000229335.11 link	c.465C>G	p.His155Gln	missense_variant	Exon 4 of 5	1	NM_020661.4	ENSP00000229335.6		Q9GZX7-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461038

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726810

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33408

American (AMR)

AF:

0.00

AC:

AN:

44538

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26102

East Asian (EAS)

AF:

0.00

AC:

AN:

39672

South Asian (SAS)

AF:

0.00

AC:

AN:

86096

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53322

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5712

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111838

Other (OTH)

AF:

0.0000166

AC:

AN:

60350

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.074

BayesDel_addAF

Benign

-0.22

BayesDel_noAF

Benign

-0.55

CADD

Benign

0.099

(source)

DANN

Benign

0.35

DEOGEN2

Benign

0.15

T;.

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.043

LIST_S2

Benign

0.63

T;T

M_CAP

Benign

0.0081

MetaRNN

Benign

0.031

T;T

MetaSVM

Benign

-0.99

MutationAssessor

Benign

-1.8

N;.

PhyloP100

-0.16

PrimateAI

Benign

0.27

PROVEAN

Benign

1.8

N;N

REVEL

Benign

0.13

Sift

Benign

1.0

T;T

Sift4G

Benign

1.0

T;T

Polyphen

0.0

B;.

Vest4

0.18

MutPred

0.34

Loss of ubiquitination at K160 (P = 0.0877);.;

MVP

0.56

MPC

0.80

ClinPred

0.22

GERP RS

-0.24

Varity_R

0.14

gMVP

0.25

Mutation Taster

=89/11

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over