20-37803011-G-T

Position:

• chr20-37803011-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_030877.5(CTNNBL1):​c.1176G>T​(p.Lys392Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000109 in 1,461,828 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000011 (0 hom.)
• Consequence: CTNNBL1 NM_030877.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.46

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]

CTNNBL1 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CTNNBL1	NM_030877.5	c.1176G>T	p.Lys392Asn	missense_variant	11/16	ENST00000361383.11	NP_110517.2
CTNNBL1	NM_001281495.2	c.1095G>T	p.Lys365Asn	missense_variant	12/17		NP_001268424.1
CTNNBL1	XM_024451947.2	c.1095G>T	p.Lys365Asn	missense_variant	12/17		XP_024307715.1
CTNNBL1	XM_011528917.3	c.846G>T	p.Lys282Asn	missense_variant	9/14		XP_011527219.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CTNNBL1	ENST00000361383.11	c.1176G>T	p.Lys392Asn	missense_variant	11/16	1	NM_030877.5	ENSP00000355050.6
CTNNBL1	ENST00000628103.2	c.1095G>T	p.Lys365Asn	missense_variant	12/17	2		ENSP00000487198.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.0000109 AC: 16 AN: 1461828 Hom.: 0 Cov.: 31 AF XY: 0.00000963 AC XY: 7 AN XY: 727204

Gnomad4 AFR exome AF: 0.0000597

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000126

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

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

Dec 13, 2022

The c.1176G>T (p.K392N) alteration is located in exon 11 (coding exon 11) of the CTNNBL1 gene. This alteration results from a G to T substitution at nucleotide position 1176, causing the lysine (K) at amino acid position 392 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	0.69
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.41
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.54	.;.;D;.;.;.
Eigen	Benign	0.12
Eigen_PC	Benign	0.071
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.82	T;T;T;.;T;T
M_CAP	Benign	0.046	D
MetaRNN	Uncertain	0.61	D;D;D;D;D;D
MetaSVM	Benign	-0.80	T
MutationAssessor	Pathogenic	3.1	.;.;M;.;.;.
PrimateAI	Pathogenic	0.85	D
PROVEAN	Uncertain	-3.1	.;D;D;.;D;D
REVEL	Benign	0.26
Sift	Uncertain	0.024	.;D;D;.;D;D
Sift4G	Uncertain	0.013	D;D;D;D;D;D
Polyphen		0.97, 0.95	.;.;D;.;P;.
Vest4		0.62
MutPred		0.45		.;.;Loss of methylation at K392 (P = 0.0037);.;.;.;
MVP		0.57
MPC		1.0
ClinPred		0.98	D
GERP RS		0.93
Varity_R		0.67
gMVP		0.62

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: rs200874158; hg19: chr20-36431413;