6-57172789-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 4P and 4B. PM1PM2BP4_Strong

The NM_004282.4(BAG2):c.92G>T(p.Ser31Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000831 in 1,564,718 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000078 ( 1 hom. )

Consequence

BAG2
NM_004282.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.27

Variant links:

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]

BAG2 links:

ZNF451-AS1 (HGNC:53824): (ZNF451 regulatory antisense RNA 1)

ZNF451-AS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM1

In a modified_residue Phosphoserine (size 0) in uniprot entity BAG2_HUMAN

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.038123727).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BAG2	NM_004282.4 linkuse as main transcript	c.92G>T	p.Ser31Ile	missense_variant	1/3	ENST00000370693.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BAG2	ENST00000370693.5 linkuse as main transcript	c.92G>T	p.Ser31Ile	missense_variant	1/3	1	NM_004282.4	P1	O95816-1
ZNF451-AS1	ENST00000585414.1 linkuse as main transcript	n.605+587C>A		intron_variant, non_coding_transcript_variant		5
ZNF451-AS1	ENST00000609545.1 linkuse as main transcript	n.56+291C>A		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152178

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000164

AC:

AN:

183448

Hom.:

AF XY:

0.0000297

AC XY:

AN XY:

100960

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000127

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000779

AC:

AN:

1412540

Hom.:

Cov.:

AF XY:

0.00000999

AC XY:

AN XY:

700766

show subpopulations

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:

0.000138

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152178

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74364

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000414

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

ExAC

AF:

0.0000249

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3476

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 27, 2021

The c.92G>T (p.S31I) alteration is located in exon 1 (coding exon 1) of the BAG2 gene. This alteration results from a G to T substitution at nucleotide position 92, causing the serine (S) at amino acid position 31 to be replaced by an isoleucine (I). 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

0.31

BayesDel_addAF

Benign

-0.22

BayesDel_noAF

Benign

-0.31

Cadd

Benign

Dann

Benign

0.93

DEOGEN2

Benign

0.081

Eigen

Benign

-0.31

Eigen_PC

Benign

-0.080

FATHMM_MKL

Benign

0.65

LIST_S2

Benign

0.77

M_CAP

Uncertain

0.28

MetaRNN

Benign

0.038

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.28

MutationTaster

Benign

0.97

PrimateAI

Pathogenic

0.83

PROVEAN

Benign

1.2

REVEL

Benign

0.081

Sift

Benign

1.0

Sift4G

Benign

0.25

Polyphen

0.011

Vest4

0.22

MutPred

0.28

Loss of disorder (P = 0.0334);

MVP

0.57

MPC

0.38

ClinPred

0.21

GERP RS

4.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.26

gMVP

0.47

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over