20-37859902-A-G

Variant names:

• chr20-37859902-A-G
• rs201986512
• NM_030877.5:c.1396A>G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 5P and 1B. PS1_Moderate PM2 PP5 BP4

The NM_030877.5(CTNNBL1):​c.1396A>G​(p.Met466Val) variant causes a missense change. The variant allele was found at a frequency of 0.00000496 in 1,614,002 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely pathogenic in UniProt.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: CTNNBL1 NM_030877.5 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 5.24

Genes affected

CTNNBL1 (HGNC:15879): (catenin beta like 1) The protein encoded by this gene is a component of the pre-mRNA-processing factor 19-cell division cycle 5-like (PRP19-CDC5L) protein complex, which activates pre-mRNA splicing and is an integral part of the spliceosome. The encoded protein is also a nuclear localization sequence binding protein, and binds to activation-induced deaminase and is important for antibody diversification. This gene may also be associated with the development of obesity. Alternative splicing results in multiple transcript variants. A pseudogene of this gene has been defined on the X chromosome. [provided by RefSeq, Jul 2013]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PS1: Transcript NM_030877.5 (CTNNBL1) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in UniProt
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 20-37859902-A-G is Pathogenic according to our data. Variant chr20-37859902-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 1686824.Status of the report is no_assertion_criteria_provided, 0 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.10183969). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CTNNBL1	NM_030877.5	c.1396A>G	p.Met466Val	missense_variant	Exon 14 of 16	ENST00000361383.11	NP_110517.2
CTNNBL1	NM_001281495.2	c.1315A>G	p.Met439Val	missense_variant	Exon 15 of 17		NP_001268424.1
CTNNBL1	XM_024451947.2	c.1315A>G	p.Met439Val	missense_variant	Exon 15 of 17		XP_024307715.1
CTNNBL1	XM_011528917.3	c.1066A>G	p.Met356Val	missense_variant	Exon 12 of 14		XP_011527219.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CTNNBL1	ENST00000361383.11	c.1396A>G	p.Met466Val	missense_variant	Exon 14 of 16	1	NM_030877.5	ENSP00000355050.6
CTNNBL1	ENST00000628103.2	c.1315A>G	p.Met439Val	missense_variant	Exon 15 of 17	2		ENSP00000487198.1

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152212 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00000797 AC: 2 AN: 251050 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135698

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000410 AC: 6 AN: 1461672 Hom.: 0 Cov.: 31 AF XY: 0.00000688 AC XY: 5 AN XY: 727136

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000447

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152330 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74484

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Immunodeficiency 99 with hypogammaglobulinemia and autoimmune cytopenias Pathogenic:1

Apr 27, 2022

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	19
DANN	Benign	0.96
DEOGEN2	Benign	0.16	.;.;T;.;.;.
Eigen	Benign	-0.19
Eigen_PC	Benign	-0.041
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Benign	0.77	T;T;T;.;T;T
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.10	T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.5	.;.;M;.;.;.
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-0.67	.;N;N;.;N;N
REVEL	Benign	0.092
Sift	Benign	0.21	.;T;T;.;T;T
Sift4G	Benign	0.31	T;T;T;T;T;T
Polyphen		0.0010, 0.0020	.;.;B;.;B;.
Vest4		0.55
MVP		0.39
MPC		0.45
ClinPred		0.39	T
GERP RS		4.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.24
gMVP		0.43

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: rs201986512; hg19: chr20-36488304;