ENST00000449228.5:c.229C>G

Variant names:

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

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The ENST00000449228.5(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. 14/19 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 ENST00000449228.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.876

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

Verdict is Likely_benign. Variant got -2 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BBC3	NM_014417.5	c.126C>G	p.Pro42Pro	synonymous_variant	Exon 2 of 4	ENST00000439096.3	NP_055232.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BBC3	ENST00000449228.5	c.229C>G	p.Arg77Gly	missense_variant	Exon 2 of 4	1		ENSP00000404503.1
BBC3	ENST00000439096.3	c.126C>G	p.Pro42Pro	synonymous_variant	Exon 2 of 4	1	NM_014417.5	ENSP00000395862.2
BBC3	ENST00000341983.8	c.89-1552C>G		intron_variant	Intron 1 of 2	1		ENSP00000341155.4
BBC3	ENST00000300880.11	c.88+4209C>G		intron_variant	Intron 1 of 1	1		ENSP00000300880.7

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 31

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

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
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

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

Other links and lift over

dbSNP: rs994270563; hg19: chr19-47731563;