6-57183931-A-G

Variant names:

• chr6-57183931-A-G
• NM_004282.4:c.377A>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_004282.4(BAG2):​c.377A>G​(p.Asp126Gly) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: BAG2 NM_004282.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.23
• Publications: 0 publications found

Genes affected

BAG2 (HGNC:938): (BAG cochaperone 2) BAG proteins compete with Hip for binding to the Hsc70/Hsp70 ATPase domain and promote substrate release. All the BAG proteins have an approximately 45-amino acid BAG domain near the C terminus but differ markedly in their N-terminal regions. The predicted BAG2 protein contains 211 amino acids. The BAG domains of BAG1, BAG2, and BAG3 interact specifically with the Hsc70 ATPase domain in vitro and in mammalian cells. All 3 proteins bind with high affinity to the ATPase domain of Hsc70 and inhibit its chaperone activity in a Hip-repressible manner. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BAG2	NM_004282.4	c.377A>G	p.Asp126Gly	missense_variant	Exon 3 of 3	ENST00000370693.5	NP_004273.1
BAG2	XM_005249490.5	c.278A>G	p.Asp93Gly	missense_variant	Exon 4 of 4		XP_005249547.1
BAG2	XM_011514999.4	c.278A>G	p.Asp93Gly	missense_variant	Exon 4 of 4		XP_011513301.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BAG2	ENST00000370693.5	c.377A>G	p.Asp126Gly	missense_variant	Exon 3 of 3	1	NM_004282.4	ENSP00000359727.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

May 13, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.377A>G (p.D126G) alteration is located in exon 3 (coding exon 3) of the BAG2 gene. This alteration results from a A to G substitution at nucleotide position 377, causing the aspartic acid (D) at amino acid position 126 to be replaced by a glycine (G). 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	0.10
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.040
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.15	T
Eigen	Uncertain	0.52
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.88	D
M_CAP	Benign	0.074	D
MetaRNN	Uncertain	0.45	T
MetaSVM	Uncertain	0.38	D
MutationAssessor	Uncertain	2.3	M
PhyloP100		6.2
PrimateAI	Benign	0.43	T
PROVEAN	Uncertain	-2.6	D
REVEL	Uncertain	0.57
Sift	Uncertain	0.020	D
Sift4G	Uncertain	0.018	D
Polyphen		0.98	D
Vest4		0.39
MutPred		0.51		Loss of stability (P = 0.0259);
MVP		0.90
MPC		0.44
ClinPred		0.92	D
GERP RS		6.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.21
gMVP		0.57
Mutation Taster		=58/42	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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

hg19: chr6-57048729;