2-111161417-A-G

Position:

• chr2-111161417-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_138621.5(BCL2L11):​c.499-2716A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00419 in 1,550,550 control chromosomes in the GnomAD database, including 213 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.022 (124 hom., cov: 32)
  • Exomes 𝑓: 0.0022 (89 hom.)
• Consequence: BCL2L11 NM_138621.5 intron
• Scores: Splicing: ADA: 0.0002852
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.118

Genes affected

BCL2L11 (HGNC:994): (BCL2 like 11) The protein encoded by this gene belongs to the BCL-2 protein family. BCL-2 family members form hetero- or homodimers and act as anti- or pro-apoptotic regulators that are involved in a wide variety of cellular activities. The protein encoded by this gene contains a Bcl-2 homology domain 3 (BH3). It has been shown to interact with other members of the BCL-2 protein family and to act as an apoptotic activator. The expression of this gene can be induced by nerve growth factor (NGF), as well as by the forkhead transcription factor FKHR-L1, which suggests a role of this gene in neuronal and lymphocyte apoptosis. Transgenic studies of the mouse counterpart suggested that this gene functions as an essential initiator of apoptosis in thymocyte-negative selection. Several alternatively spliced transcript variants of this gene have been identified. [provided by RefSeq, Jun 2013]

MIR4435-2HG (HGNC:35163): (MIR4435-2 host gene)

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_addAF=-0.791147).
• BP6: Variant 2-111161417-A-G is Benign according to our data. Variant chr2-111161417-A-G is described in ClinVar as [Benign]. Clinvar id is 1242068.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0738 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BCL2L11	NM_138621.5	c.499-2716A>G		intron_variant		ENST00000393256.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BCL2L11	ENST00000393256.8	c.499-2716A>G		intron_variant		1	NM_138621.5	P1
MIR4435-2HG	ENST00000645030.2	n.453-124495T>C		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.0220 AC: 3346 AN: 152212 Hom.: 124 Cov.: 32

Gnomad AFR AF: 0.0761

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00850

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000620

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.000338

Gnomad OTH AF: 0.0143

GnomAD3 exomes AF: 0.00436 AC: 651 AN: 149190 Hom.: 16 AF XY: 0.00353 AC XY: 284 AN XY: 80360

Gnomad AFR exome AF: 0.0781

Gnomad AMR exome AF: 0.00358

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000177

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000272

Gnomad OTH exome AF: 0.00371

GnomAD4 exome AF: 0.00225 AC: 3145 AN: 1398220 Hom.: 89 Cov.: 30 AF XY: 0.00199 AC XY: 1372 AN XY: 689638

Gnomad4 AFR exome AF: 0.0781

Gnomad4 AMR exome AF: 0.00490

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000114

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000170

Gnomad4 OTH exome AF: 0.00514

GnomAD4 genome AF: 0.0220 AC: 3349 AN: 152330 Hom.: 124 Cov.: 32 AF XY: 0.0203 AC XY: 1509 AN XY: 74488

Gnomad4 AFR AF: 0.0760

Gnomad4 AMR AF: 0.00849

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000621

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000338

Gnomad4 OTH AF: 0.0142

Alfa AF: 0.0139 Hom.: 30

Bravo AF: 0.0250

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ExAC AF: 0.00283 AC: 78

Asia WGS AF: 0.00433 AC: 15 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 28, 2020	This variant is associated with the following publications: (PMID: 30924900) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.79	T
BayesDel_noAF	Benign	-0.85
CADD	Benign	8.9
DANN	Benign	0.75
Eigen	Benign	-0.56
Eigen_PC	Benign	-0.75
FATHMM_MKL	Benign	0.020	N
MutationTaster	Benign	0.99	N;N;N
GERP RS		1.9

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00029
dbscSNV1_RF	Benign	0.0
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: rs76245002; hg19: chr2-111918994;