1-85270792-G-C

Variant names:

• chr1-85270792-G-C
• rs121918314
• NM_003921.5:c.172C>G

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP5

The NM_003921.5(BCL10):​c.172C>G​(p.Arg58Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R58Q) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: BCL10 NM_003921.5 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 2.94
• Publications: 6 publications found

Genes affected

BCL10 (HGNC:989): (BCL10 immune signaling adaptor) This gene was identified by its translocation in a case of mucosa-associated lymphoid tissue (MALT) lymphoma. The protein encoded by this gene contains a caspase recruitment domain (CARD), and has been shown to induce apoptosis and to activate NF-kappaB. This protein is reported to interact with other CARD domain containing proteins including CARD9, 10, 11 and 14, which are thought to function as upstream regulators in NF-kappaB signaling. This protein is found to form a complex with MALT1, a protein encoded by another gene known to be translocated in MALT lymphoma. MALT1 and this protein are thought to synergize in the activation of NF-kappaB, and the deregulation of either of them may contribute to the same pathogenetic process that leads to the malignancy. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Mar 2016]

BCL10 Gene-Disease associations (from GenCC):

• immunodeficiency 37

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: ClinGen, Ambry Genetics, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 1-85270792-G-C is Pathogenic according to our data. Variant chr1-85270792-G-C is described in ClinVar as Pathogenic. ClinVar VariationId is 6265.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003921.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BCL10	NM_003921.5	MANE Select	c.172C>G	p.Arg58Gly	missense	Exon 2 of 3	NP_003912.1	O95999
	BCL10	NM_001320715.2		c.172C>G	p.Arg58Gly	missense	Exon 2 of 3	NP_001307644.1	A0A087WWW9

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BCL10	ENST00000648566.1	MANE Select	c.172C>G	p.Arg58Gly	missense	Exon 2 of 3	ENSP00000498104.1	O95999
	BCL10	ENST00000913809.1		c.169C>G	p.Arg57Gly	missense	Exon 2 of 3	ENSP00000583868.1
	BCL10	ENST00000620248.3	TSL:5	c.172C>G	p.Arg58Gly	missense	Exon 2 of 3	ENSP00000480561.2	A0A087WWW9

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	MALE GERM CELL TUMOR, SOMATIC (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.88
BayesDel_addAF	Uncertain	0.089	D
BayesDel_noAF	Benign	-0.11
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.49	T
Eigen	Uncertain	0.53
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.92	D
M_CAP	Benign	0.0086	T
MetaRNN	Uncertain	0.46	T
MetaSVM	Benign	-1.2	T
MutationAssessor	Benign	1.7	L
PhyloP100		2.9
PrimateAI	Uncertain	0.64	T
PROVEAN	Pathogenic	-5.3	D
REVEL	Benign	0.20
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.0080	D
Polyphen		0.90	P
Vest4		0.51
MutPred		0.46		Loss of MoRF binding (P = 0.0329)
MVP		0.80
MPC		1.8
ClinPred		0.99	D
GERP RS		5.0
Varity_R		0.87
gMVP		0.63
Mutation Taster		=19/81	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs121918314; hg19: chr1-85736475;