Genetic Variant ENST00000246785:c.-462G>T (chr19-49665614-G-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The ENST00000246785.7(BCL2L12):c.-462G>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000022 in 453,990 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000022 ( 0 hom. )

Consequence

BCL2L12
ENST00000246785.7 5_prime_UTR_premature_start_codon_gain

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.330

Publications

49 publications found

Variant links:

Genes affected

BCL2L12 (HGNC:13787): (BCL2 like 12) This gene encodes a member of a family of proteins containing a Bcl-2 homology domain 2 (BH2). The encoded protein is an anti-apoptotic factor that acts as an inhibitor of caspases 3 and 7 in the cytoplasm. In the nucleus, it binds to the p53 tumor suppressor protein, preventing its association with target genes. Overexpression of this gene has been detected in a number of different cancers. There is a pseudogene for this gene on chromosome 3. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Sep 2013]

BCL2L12 links:

IRF3 (HGNC:6118): (interferon regulatory factor 3) This gene encodes a member of the interferon regulatory transcription factor (IRF) family. The encoded protein is found in an inactive cytoplasmic form that upon serine/threonine phosphorylation forms a complex with CREBBP. This complex translocates to the nucleus and activates the transcription of interferons alpha and beta, as well as other interferon-induced genes. The protein plays an important role in the innate immune response against DNA and RNA viruses. Mutations in this gene are associated with Encephalopathy, acute, infection-induced, herpes-specific, 7. [provided by RefSeq, Sep 2020]

IRF3 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.44).

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000246785.7. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
IRF3	NM_001571.6	MANE Select	c.-9+17C>A	intron	N/A	NP_001562.1	Q14653-1
BCL2L12	NM_001282520.1		c.-210G>T	5_prime_UTR_premature_start_codon_gain	Exon 1 of 5	NP_001269449.1	Q9HB09
BCL2L12	NM_001282520.1		c.-210G>T	5_prime_UTR	Exon 1 of 5	NP_001269449.1	Q9HB09

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
BCL2L12	ENST00000246785.7	TSL:1	c.-462G>T	5_prime_UTR_premature_start_codon_gain	Exon 1 of 7	ENSP00000246785.3	Q9HB09-1
BCL2L12	ENST00000441864.6	TSL:1	c.-462G>T	5_prime_UTR_premature_start_codon_gain	Exon 1 of 7	ENSP00000393803.2	Q9HB09-3
BCL2L12	ENST00000619007.4	TSL:1	c.-462G>T	5_prime_UTR_premature_start_codon_gain	Exon 1 of 6	ENSP00000483272.2	A0A0X8AT42

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000220

AC:

AN:

453990

Hom.:

Cov.:

AF XY:

0.00000424

AC XY:

AN XY:

236074

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

12654

American (AMR)

AF:

0.00

AC:

AN:

17604

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

13052

East Asian (EAS)

AF:

0.00

AC:

AN:

29318

South Asian (SAS)

AF:

0.0000239

AC:

AN:

41838

European-Finnish (FIN)

AF:

0.00

AC:

AN:

27014

Middle Eastern (MID)

AF:

0.00

AC:

AN:

1852

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

285336

Other (OTH)

AF:

0.00

AC:

AN:

25322

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

16071

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.44

CADD

Benign

2.7

(source)

DANN

Benign

0.56

PhyloP100

-0.33

PromoterAI

-0.066

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over