rs748653573

chr3-41238067-C-Achr3-41238067-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM5 PP2 BP4_Moderate

The NM_001904.4(CTNNB1):c.2128C>A(p.Arg710Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000616 in 1,461,138 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R710H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000062 (0 hom.)
• Consequence: CTNNB1 NM_001904.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.64

Genes affected

CTNNB1 (HGNC:2514): (catenin beta 1) The protein encoded by this gene is part of a complex of proteins that constitute adherens junctions (AJs). AJs are necessary for the creation and maintenance of epithelial cell layers by regulating cell growth and adhesion between cells. The encoded protein also anchors the actin cytoskeleton and may be responsible for transmitting the contact inhibition signal that causes cells to stop dividing once the epithelial sheet is complete. Finally, this protein binds to the product of the APC gene, which is mutated in adenomatous polyposis of the colon. Mutations in this gene are a cause of colorectal cancer (CRC), pilomatrixoma (PTR), medulloblastoma (MDB), and ovarian cancer. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Aug 2016]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM5: Other missense variant is known to change same aminoacid residue: Variant chr3-41238067-C-T is described in Lovd as [Likely_pathogenic].
• PP2: Missense variant where missense usually causes diseases, CTNNB1
• BP4: Computational evidence support a benign effect (MetaRNN=0.19088176).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CTNNB1	NM_001904.4	c.2128C>A	p.Arg710Ser	missense_variant	14/15	ENST00000349496.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CTNNB1	ENST00000349496.11	c.2128C>A	p.Arg710Ser	missense_variant	14/15	1	NM_001904.4	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251354 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135846

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000616 AC: 9 AN: 1461138 Hom.: 0 Cov.: 30 AF XY: 0.00000550 AC XY: 4 AN XY: 726944

Gnomad4 AFR exome AF: 0.00

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: 0.00000810

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.34
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.0
Cadd	Uncertain	23
Dann	Benign	0.91
DEOGEN2	Benign	0.31	T;T;T;T;T;T;T;T;T;T;T;.;T;T;T;T;T;.;T;T;T;T;.;.;T;T;.;T;T;T;T;.;T;T;T;T;T;T;T
Eigen	Benign	-0.19
Eigen_PC	Benign	0.033
FATHMM_MKL	Uncertain	0.87	D
M_CAP	Benign	0.027	D
MetaRNN	Benign	0.19	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.29	N;N;.;N;N;N;N;N;.;N;N;.;.;N;N;N;.;.;.;.;N;N;.;.;N;.;.;N;N;.;N;.;N;.;N;N;N;N;N
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Pathogenic	0.82	D
Polyphen		0.0020	B;B;.;B;B;B;B;B;.;B;B;.;.;B;B;B;.;.;.;.;B;B;.;.;B;.;.;B;B;.;B;.;B;.;B;B;B;B;B
Vest4		0.91, 0.92, 0.91, 0.90, 0.91
MutPred		0.38		Loss of catalytic residue at R710 (P = 0.0082);Loss of catalytic residue at R710 (P = 0.0082);.;Loss of catalytic residue at R710 (P = 0.0082);Loss of catalytic residue at R710 (P = 0.0082);Loss of catalytic residue at R710 (P = 0.0082);Loss of catalytic residue at R710 (P = 0.0082);Loss of catalytic residue at R710 (P = 0.0082);.;Loss of catalytic residue at R710 (P = 0.0082);Loss of catalytic residue at R710 (P = 0.0082);.;.;Loss of catalytic residue at R710 (P = 0.0082);Loss of catalytic residue at R710 (P = 0.0082);Loss of catalytic residue at R710 (P = 0.0082);.;.;.;.;Loss of catalytic residue at R710 (P = 0.0082);Loss of catalytic residue at R710 (P = 0.0082);.;.;Loss of catalytic residue at R710 (P = 0.0082);.;.;Loss of catalytic residue at R710 (P = 0.0082);Loss of catalytic residue at R710 (P = 0.0082);.;Loss of catalytic residue at R710 (P = 0.0082);Loss of catalytic residue at R710 (P = 0.0082);Loss of catalytic residue at R710 (P = 0.0082);.;Loss of catalytic residue at R710 (P = 0.0082);Loss of catalytic residue at R710 (P = 0.0082);Loss of catalytic residue at R710 (P = 0.0082);Loss of catalytic residue at R710 (P = 0.0082);Loss of catalytic residue at R710 (P = 0.0082);
MVP		0.88
MPC		0.25
ClinPred		0.43	T
GERP RS		5.2
RBP_binding_hub_radar		1.1
RBP_regulation_power_radar		2.8
Varity_R		0.37
gMVP		0.51

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: rs748653573; hg19: chr3-41279558;