19-47228306-G-C

Variant names:

• chr19-47228306-G-C
• rs994270563
• ENST00000449228.5:c.229C>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001127240.3(BBC3):​c.229C>G​(p.Arg77Gly) 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. 15/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R77W) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 31)
• Consequence: BBC3 NM_001127240.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.876
• Publications: 0 publications found

Genes affected

BBC3 (HGNC:17868): (BCL2 binding component 3) This gene encodes a member of the BCL-2 family of proteins. This family member belongs to the BH3-only pro-apoptotic subclass. The protein cooperates with direct activator proteins to induce mitochondrial outer membrane permeabilization and apoptosis. It can bind to anti-apoptotic Bcl-2 family members to induce mitochondrial dysfunction and caspase activation. Because of its pro-apoptotic role, this gene is a potential drug target for cancer therapy and for tissue injury. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Dec 2011]

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.06504318).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001127240.3. 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
	BBC3	NM_014417.5	MANE Select	c.126C>G	p.Pro42Pro	synonymous	Exon 2 of 4	NP_055232.1	Q9BXH1-1
	BBC3	NM_001127240.3		c.229C>G	p.Arg77Gly	missense	Exon 2 of 4	NP_001120712.1	Q96PG8-2
	BBC3	NM_001127241.3		c.89-1552C>G		intron	N/A	NP_001120713.1	Q9BXH1-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BBC3	ENST00000449228.5	TSL:1	c.229C>G	p.Arg77Gly	missense	Exon 2 of 4	ENSP00000404503.1	Q96PG8-2
	BBC3	ENST00000439096.3	TSL:1 MANE Select	c.126C>G	p.Pro42Pro	synonymous	Exon 2 of 4	ENSP00000395862.2	Q9BXH1-1
	BBC3	ENST00000341983.8	TSL:1	c.89-1552C>G		intron	N/A	ENSP00000341155.4	Q9BXH1-2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.040	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	6.0
DANN	Benign	0.84
DEOGEN2	Benign	0.17	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.056	N
LIST_S2	Benign	0.46	T
M_CAP	Benign	0.078	D
MetaRNN	Benign	0.065	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.0	N
PhyloP100		-0.88
PROVEAN	Benign	-0.15	N
REVEL	Benign	0.020
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.42	T
Vest4		0.14
MutPred		0.28		Loss of methylation at R77 (P = 0.0317)
MVP		0.40
MPC		1.6
ClinPred		0.19	T
GERP RS		-4.9
Varity_R		0.11
gMVP		0.19
Mutation Taster		=88/12	polymorphism

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: rs994270563; hg19: chr19-47731563;