chr20-37777412-A-G

Position:

• chr20-37777412-A-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_030877.5(CTNNBL1):​c.818A>G​(p.Asn273Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000948 in 1,613,868 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000091 (0 hom.)
• Consequence: CTNNBL1 NM_030877.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.51

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.027592242).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CTNNBL1	NM_030877.5	c.818A>G	p.Asn273Ser	missense_variant	8/16	ENST00000361383.11	NP_110517.2
CTNNBL1	NM_001281495.2	c.737A>G	p.Asn246Ser	missense_variant	9/17		NP_001268424.1
CTNNBL1	XM_024451947.2	c.737A>G	p.Asn246Ser	missense_variant	9/17		XP_024307715.1
CTNNBL1	XM_011528917.3	c.488A>G	p.Asn163Ser	missense_variant	6/14		XP_011527219.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CTNNBL1	ENST00000361383.11	c.818A>G	p.Asn273Ser	missense_variant	8/16	1	NM_030877.5	ENSP00000355050.6
CTNNBL1	ENST00000628103.2	c.737A>G	p.Asn246Ser	missense_variant	9/17	2		ENSP00000487198.1

Frequencies

GnomAD3 genomes AF: 0.000131 AC: 20 AN: 152220 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000135 AC: 34 AN: 251304 Hom.: 0 AF XY: 0.000110 AC XY: 15 AN XY: 135804

Gnomad AFR exome AF: 0.000308

Gnomad AMR exome AF: 0.0000578

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.000163

Gnomad SAS exome AF: 0.000523

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000528

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000910 AC: 133 AN: 1461532 Hom.: 0 Cov.: 30 AF XY: 0.000105 AC XY: 76 AN XY: 727080

Gnomad4 AFR exome AF: 0.000120

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.000696

Gnomad4 FIN exome AF: 0.0000374

Gnomad4 NFE exome AF: 0.0000513

Gnomad4 OTH exome AF: 0.0000662

GnomAD4 genome AF: 0.000131 AC: 20 AN: 152336 Hom.: 0 Cov.: 32 AF XY: 0.000134 AC XY: 10 AN XY: 74490

Gnomad4 AFR AF: 0.000240

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00124

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000582 Hom.: 0

Bravo AF: 0.000106

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000107 AC: 13

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.00

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 21, 2023

The c.818A>G (p.N273S) alteration is located in exon 8 (coding exon 8) of the CTNNBL1 gene. This alteration results from a A to G substitution at nucleotide position 818, causing the asparagine (N) at amino acid position 273 to be replaced by a serine (S). 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	0.064
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	19
DANN	Benign	0.25
DEOGEN2	Benign	0.13	.;.;T;.;.;.
Eigen	Benign	-0.50
Eigen_PC	Benign	-0.21
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.87	D;D;D;.;D;D
M_CAP	Benign	0.0077	T
MetaRNN	Benign	0.028	T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.12	.;.;N;.;.;.
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	-0.12	.;N;N;.;N;N
REVEL	Benign	0.11
Sift	Benign	1.0	.;T;T;.;T;T
Sift4G	Benign	0.89	T;T;T;T;T;T
Polyphen		0.0, 0.0010	.;.;B;.;B;.
Vest4		0.37
MVP		0.45
MPC		0.35
ClinPred		0.044	T
GERP RS		4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.10
gMVP		0.39

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs137951659; hg19: chr20-36405814; COSMIC: COSV63743973;