6-31641834-C-A

Variant summary

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

The NM_001387994.1(BAG6):c.2447G>T(p.Arg816Leu) 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. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: BAG6 NM_001387994.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.86

Genes affected

BAG6 (HGNC:13919): (BAG cochaperone 6) This gene was first characterized as part of a cluster of genes located within the human major histocompatibility complex class III region. This gene encodes a nuclear protein that is cleaved by caspase 3 and is implicated in the control of apoptosis. In addition, the protein forms a complex with E1A binding protein p300 and is required for the acetylation of p53 in response to DNA damage. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

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, BAG6
• BP4: Computational evidence support a benign effect (MetaRNN=0.26296973).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BAG6	NM_001387994.1	c.2447G>T	p.Arg816Leu	missense_variant	17/26	ENST00000676615.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BAG6	ENST00000676615.2	c.2447G>T	p.Arg816Leu	missense_variant	17/26		NM_001387994.1	A2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 05, 2023

The c.2357G>T (p.R786L) alteration is located in exon 16 (coding exon 15) of the BAG6 gene. This alteration results from a G to T substitution at nucleotide position 2357, causing the arginine (R) at amino acid position 786 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.26
BayesDel_addAF	Benign	-0.040	T
BayesDel_noAF	Benign	-0.30
Cadd	Benign	23
Dann	Uncertain	0.99
Eigen	Benign	0.13
Eigen_PC	Benign	0.16
FATHMM_MKL	Benign	0.31	N
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.26	T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	N;N;N;N;N;N
PrimateAI	Uncertain	0.53	T
PROVEAN	Uncertain	-2.9	D;D;D;D;D
REVEL	Benign	0.14
Sift	Benign	0.066	T;T;T;D;T
Sift4G	Benign	0.43	T;T;T;T;T
Polyphen		1.0	D;D;D;.;.
Vest4		0.44
MutPred		0.34		.;.;Loss of disorder (P = 0.0531);.;.;
MVP		0.57
MPC		2.3
ClinPred		0.85	D
GERP RS		4.7
Varity_R		0.14
gMVP		0.92

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: chr6-31609611;