6-89932518-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_021813.4(BACH2):c.2416G>C(p.Glu806Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00000205 in 1,461,894 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E806D) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: BACH2 NM_021813.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.36

Genes affected

BACH2 (HGNC:14078): (BTB domain and CNC homolog 2) Enables sequence-specific double-stranded DNA binding activity. Involved in primary adaptive immune response involving T cells and B cells. Located in cytosol and nucleoplasm. Implicated in immunodeficiency 60. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, BACH2
• BP4: Computational evidence support a benign effect (MetaRNN=0.12074801).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BACH2	NM_021813.4	c.2416G>C	p.Glu806Gln	missense_variant	9/9	ENST00000257749.9
BACH2	NM_001170794.2	c.2416G>C	p.Glu806Gln	missense_variant	7/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BACH2	ENST00000257749.9	c.2416G>C	p.Glu806Gln	missense_variant	9/9	1	NM_021813.4	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461894 Hom.: 0 Cov.: 30 AF XY: 0.00000275 AC XY: 2 AN XY: 727248

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Immunodeficiency 60 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Neuberg Centre For Genomic Medicine, NCGM

Feb 14, 2023

The missense variant c.2416G>C(p.Glu806Gln) in BACH2 gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The variant is novel (not in any individuals) in gnomAD Exomes and 1000 Genomes. The amino acid Glutamic acid at position 806 is changed to a Glutamine changing protein sequence and it might alter its composition and physico-chemical properties. The amino acid change p.Glu806Gln in BACH2 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.087
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.59
Cadd	Benign	21
Dann	Benign	0.97
DEOGEN2	Benign	0.12	T;T;T
Eigen	Benign	-0.028
Eigen_PC	Benign	0.14
FATHMM_MKL	Uncertain	0.95	D
M_CAP	Benign	0.0070	T
MetaRNN	Benign	0.12	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.5	L;L;L
MutationTaster	Benign	0.98	D;D;D
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-0.35	N;N;N
REVEL	Benign	0.076
Sift	Benign	0.19	T;T;T
Sift4G	Benign	0.31	T;T;T
Polyphen		0.010	B;B;B
Vest4		0.078
MutPred		0.10		Gain of helix (P = 0.0199);Gain of helix (P = 0.0199);Gain of helix (P = 0.0199);
MVP		0.52
MPC		0.51
ClinPred		0.52	D
GERP RS		5.5
Varity_R		0.14
gMVP		0.36

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr6-90642237;