chr3-187722593-C-A

Position:

• chr3-187722593-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001706.5(BCL6):​c.1986G>T​(p.Lys662Asn) 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. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: BCL6 NM_001706.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.04

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 Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.37933964).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BCL6	NM_001706.5	c.1986G>T	p.Lys662Asn	missense_variant	10/10	ENST00000406870.7
LOC100131635	NR_034062.1	n.293+6853C>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BCL6	ENST00000406870.7	c.1986G>T	p.Lys662Asn	missense_variant	10/10	1	NM_001706.5	P1
	ENST00000449623.5	n.346+6853C>A		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

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

Jun 29, 2023

The c.1986G>T (p.K662N) alteration is located in exon 10 (coding exon 8) of the BCL6 gene. This alteration results from a G to T substitution at nucleotide position 1986, causing the lysine (K) at amino acid position 662 to be replaced by an asparagine (N). 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	Pathogenic	0.92
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.44
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.53	.;D;D;.
Eigen	Benign	0.16
Eigen_PC	Benign	0.17
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.85	T;.;T;.
M_CAP	Benign	0.030	D
MetaRNN	Benign	0.38	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.72	.;N;N;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.93	D
PROVEAN	Uncertain	-2.5	.;N;N;N
REVEL	Benign	0.16
Sift	Uncertain	0.011	.;D;D;T
Sift4G	Benign	0.17	T;T;T;T
Polyphen		1.0	.;D;D;.
Vest4		0.53
MutPred		0.46		.;Loss of methylation at K662 (P = 2e-04);Loss of methylation at K662 (P = 2e-04);.;
MVP		0.65
MPC		2.8
ClinPred		0.88	D
GERP RS		3.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.7
Varity_R		0.37
gMVP		0.78

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs1478407186; hg19: chr3-187440381;