rs2234962

Variant names:

• chr10-119670121-T-C
• rs2234962
• NM_004281.4:c.451T>C

Your query was ambiguous. Multiple possible variants found:

• chr10-119670121-T-C
• chr10-119670121-T-G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_004281.4(BAG3):​c.451T>C​(p.Cys151Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.195 in 1,613,424 control chromosomes in the GnomAD database, including 33,563 homozygotes. 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 Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C151Y) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.15 (2112 hom., cov: 33)
  • Exomes 𝑓: 0.20 (31451 hom.)
• Consequence: BAG3 NM_004281.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:17
• Conservation: PhyloP100: 0.566
• Publications: 103 publications found

Genes affected

BAG3 (HGNC:939): (BAG cochaperone 3) 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 protein encoded by this gene contains a WW domain in the N-terminal region and a BAG domain in the C-terminal region. 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]

BAG3 Gene-Disease associations (from GenCC):

• dilated cardiomyopathy

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• dilated cardiomyopathy 1HH

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• myofibrillar myopathy

  Inheritance: Unknown, AD Classification: DEFINITIVE Submitted by: ClinGen, G2P
• myofibrillar myopathy 6

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), Orphanet
• familial isolated dilated cardiomyopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Charcot-Marie-tooth disease, axonal, type 2JJ

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
• distal hereditary motor neuropathy

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.001447022).
• BP6: Variant 10-119670121-T-C is Benign according to our data. Variant chr10-119670121-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 44783.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.205 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004281.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BAG3	NM_004281.4	MANE Select	c.451T>C	p.Cys151Arg	missense	Exon 2 of 4	NP_004272.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BAG3	ENST00000369085.8	TSL:1 MANE Select	c.451T>C	p.Cys151Arg	missense	Exon 2 of 4	ENSP00000358081.4	O95817
	BAG3	ENST00000889977.1		c.451T>C	p.Cys151Arg	missense	Exon 3 of 5	ENSP00000560036.1
	BAG3	ENST00000889978.1		c.451T>C	p.Cys151Arg	missense	Exon 2 of 4	ENSP00000560037.1

Frequencies

GnomAD3 genomes AF: 0.147 AC: 22296 AN: 152058 Hom.: 2111 Cov.: 33

Gnomad AFR AF: 0.0368

Gnomad AMI AF: 0.193

Gnomad AMR AF: 0.130

Gnomad ASJ AF: 0.213

Gnomad EAS AF: 0.00289

Gnomad SAS AF: 0.201

Gnomad FIN AF: 0.227

Gnomad MID AF: 0.130

Gnomad NFE AF: 0.208

Gnomad OTH AF: 0.139

GnomAD2 exomes AF: 0.173 AC: 43222 AN: 249702 AF XY: 0.181

Gnomad AFR exome AF: 0.0354

Gnomad AMR exome AF: 0.100

Gnomad ASJ exome AF: 0.221

Gnomad EAS exome AF: 0.00109

Gnomad FIN exome AF: 0.228

Gnomad NFE exome AF: 0.218

Gnomad OTH exome AF: 0.184

GnomAD4 exome AF: 0.200 AC: 292948 AN: 1461248 Hom.: 31451 Cov.: 39 AF XY: 0.202 AC XY: 147111 AN XY: 726872

African (AFR) AF: 0.0305 AC: 1021 AN: 33478

American (AMR) AF: 0.102 AC: 4581 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.214 AC: 5598 AN: 26126

East Asian (EAS) AF: 0.00111 AC: 44 AN: 39682

South Asian (SAS) AF: 0.215 AC: 18505 AN: 86246

European-Finnish (FIN) AF: 0.223 AC: 11870 AN: 53138

Middle Eastern (MID) AF: 0.188 AC: 1082 AN: 5766

European-Non Finnish (NFE) AF: 0.215 AC: 238943 AN: 1111720

Other (OTH) AF: 0.187 AC: 11304 AN: 60372

GnomAD4 genome AF: 0.147 AC: 22298 AN: 152176 Hom.: 2112 Cov.: 33 AF XY: 0.147 AC XY: 10956 AN XY: 74406

African (AFR) AF: 0.0368 AC: 1526 AN: 41518

American (AMR) AF: 0.130 AC: 1984 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.213 AC: 738 AN: 3466

East Asian (EAS) AF: 0.00289 AC: 15 AN: 5182

South Asian (SAS) AF: 0.202 AC: 974 AN: 4818

European-Finnish (FIN) AF: 0.227 AC: 2404 AN: 10592

Middle Eastern (MID) AF: 0.129 AC: 38 AN: 294

European-Non Finnish (NFE) AF: 0.208 AC: 14153 AN: 67984

Other (OTH) AF: 0.137 AC: 290 AN: 2112

Alfa AF: 0.188 Hom.: 12966

Bravo AF: 0.133

TwinsUK AF: 0.210 AC: 777

ALSPAC AF: 0.210 AC: 808

ESP6500AA AF: 0.0414 AC: 182

ESP6500EA AF: 0.207 AC: 1782

ExAC AF: 0.175 AC: 21195

Asia WGS AF: 0.0740 AC: 260 AN: 3478

EpiCase AF: 0.210

EpiControl AF: 0.208

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	10	not specified (10)
-	-	2	Myofibrillar myopathy 6 (2)
-	-	2	not provided (2)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Dilated cardiomyopathy 1HH (1)
-	-	1	Myofibrillar myopathy 6;C3151293:Dilated cardiomyopathy 1HH (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	17
DANN	Uncertain	0.99
DEOGEN2	Benign	0.30	T
Eigen	Benign	-0.51
Eigen_PC	Benign	-0.45
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Benign	0.44	T
MetaRNN	Benign	0.0014	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.3	L
PhyloP100		0.57
PrimateAI	Uncertain	0.48	T
PROVEAN	Benign	-1.7	N
REVEL	Benign	0.28
Sift	Uncertain	0.020	D
Sift4G	Uncertain	0.0080	D
Polyphen		0.66	P
Vest4		0.20
MPC		0.50
ClinPred		0.032	T
GERP RS		0.064
Varity_R		0.33
gMVP		0.42
Mutation Taster		=81/19	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2234962; hg19: chr10-121429633; COSMIC: COSV64841867;