6-89932506-G-A

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.2428C>T(p.Pro810Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: BACH2 NM_021813.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.66

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=0.073721826).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BACH2	NM_021813.4	c.2428C>T	p.Pro810Ser	missense_variant	9/9	ENST00000257749.9
BACH2	NM_001170794.2	c.2428C>T	p.Pro810Ser	missense_variant	7/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BACH2	ENST00000257749.9	c.2428C>T	p.Pro810Ser	missense_variant	9/9	1	NM_021813.4	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Sep 23, 2021

This sequence change replaces proline with serine at codon 810 of the BACH2 protein (p.Pro810Ser). The proline residue is moderately conserved and there is a moderate physicochemical difference between proline and serine. This variant has not been reported in the literature in individuals affected with BACH2-related conditions. This variant is not present in population databases (ExAC no frequency). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The serine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.060
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.57
Cadd	Benign	17
Dann	Benign	0.81
DEOGEN2	Benign	0.067	T;T;T
Eigen	Benign	-0.21
Eigen_PC	Benign	0.013
FATHMM_MKL	Uncertain	0.78	D
M_CAP	Benign	0.0037	T
MetaRNN	Benign	0.074	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.32	N;N;N
MutationTaster	Benign	0.78	D;D;D
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-0.56	N;N;N
REVEL	Benign	0.049
Sift	Benign	0.58	T;T;T
Sift4G	Benign	0.80	T;T;T
Polyphen		0.0010	B;B;B
Vest4		0.067
MutPred		0.087		Loss of catalytic residue at P809 (P = 0.0131);Loss of catalytic residue at P809 (P = 0.0131);Loss of catalytic residue at P809 (P = 0.0131);
MVP		0.34
MPC		0.52
ClinPred		0.34	T
GERP RS		4.5
Varity_R		0.078
gMVP		0.22

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr6-90642225;