3-187729201-G-A

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 1P and 6B. PP2 BP4_Moderate BS2

The NM_001706.5(BCL6):c.1204C>T(p.Arg402Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000241 in 1,454,080 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R402H) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000024 (0 hom.)
• Consequence: BCL6 NM_001706.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.65

Genes affected

BCL6 (HGNC:1001): (BCL6 transcription repressor) The protein encoded by this gene is a zinc finger transcription factor and contains an N-terminal POZ domain. This protein acts as a sequence-specific repressor of transcription, and has been shown to modulate the transcription of STAT-dependent IL-4 responses of B cells. This protein can interact with a variety of POZ-containing proteins that function as transcription corepressors. This gene is found to be frequently translocated and hypermutated in diffuse large-cell lymphoma (DLCL), and may be involved in the pathogenesis of DLCL. Alternatively spliced transcript variants encoding different protein isoforms have been found for this gene. [provided by RefSeq, Aug 2015]

(HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -5 ACMG points.

• PP2: Missense variant where missense usually causes diseases, BCL6
• BP4: Computational evidence support a benign effect (MetaRNN=0.25494707).
• BS2: High AC in GnomAdExome at 8 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BCL6	NM_001706.5	c.1204C>T	p.Arg402Cys	missense_variant	5/10	ENST00000406870.7
LOC100131635	NR_034062.1	n.294-3170G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BCL6	ENST00000406870.7	c.1204C>T	p.Arg402Cys	missense_variant	5/10	1	NM_001706.5	P1
	ENST00000449623.5	n.347-4323G>A		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000320 AC: 8 AN: 249986 Hom.: 0 AF XY: 0.0000370 AC XY: 5 AN XY: 135080

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000292

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000989

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000353

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000241 AC: 35 AN: 1454080 Hom.: 0 Cov.: 31 AF XY: 0.0000318 AC XY: 23 AN XY: 723194

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000454

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000824

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000226

Gnomad4 OTH exome AF: 0.0000167

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000659 Hom.: 0

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 23, 2023

The c.1204C>T (p.R402C) alteration is located in exon 5 (coding exon 3) of the BCL6 gene. This alteration results from a C to T substitution at nucleotide position 1204, causing the arginine (R) at amino acid position 402 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.37
Cadd	Pathogenic	26
Dann	Uncertain	1.0
Eigen	Uncertain	0.45
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.94	D;.;D;.
M_CAP	Benign	0.0069	T
MetaRNN	Benign	0.25	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.34	N;N;N;N
MutationTaster	Benign	0.97	D;D;D
PrimateAI	Uncertain	0.59	T
Sift4G	Uncertain	0.041	D;D;D;D
Polyphen		0.99	.;D;D;.
Vest4		0.47
MutPred		0.29		Gain of glycosylation at S404 (P = 0.026);Gain of glycosylation at S404 (P = 0.026);Gain of glycosylation at S404 (P = 0.026);Gain of glycosylation at S404 (P = 0.026);
MVP		0.51
MPC		0.43
ClinPred		0.18	T
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.11
gMVP		0.30

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: rs769386051; hg19: chr3-187446989; COSMIC: COSV51653661; COSMIC: COSV51653661;