chr1-9871229-T-C

Position:

• chr1-9871229-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_020248.3(CTNNBIP1):​c.145A>G​(p.Asn49Asp) variant causes a missense change. The variant allele was found at a frequency of 0.000000699 in 1,429,614 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 11/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: CTNNBIP1 NM_020248.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.12

Genes affected

CTNNBIP1 (HGNC:16913): (catenin beta interacting protein 1) The protein encoded by this gene binds CTNNB1 and prevents interaction between CTNNB1 and TCF family members. The encoded protein is a negative regulator of the Wnt signaling pathway. Two transcript variants encoding the same protein have been found for this gene. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2509811).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CTNNBIP1	NM_020248.3	c.145A>G	p.Asn49Asp	missense_variant	5/6	ENST00000377263.6	NP_064633.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CTNNBIP1	ENST00000377263.6	c.145A>G	p.Asn49Asp	missense_variant	5/6	1	NM_020248.3	ENSP00000366474.1
CTNNBIP1	ENST00000400904.7	c.145A>G	p.Asn49Asp	missense_variant	4/5	1		ENSP00000383696.3
CTNNBIP1	ENST00000377256.1	c.145A>G	p.Asn49Asp	missense_variant	4/5	5		ENSP00000366466.1
CTNNBIP1	ENST00000377258.5	c.145A>G	p.Asn49Asp	missense_variant	4/5	3		ENSP00000366468.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.99e-7 AC: 1 AN: 1429614 Hom.: 0 Cov.: 31 AF XY: 0.00000141 AC XY: 1 AN XY: 707706

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: 9.12e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000838 AC: 1

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

May 26, 2022

The c.145A>G (p.N49D) alteration is located in exon 5 (coding exon 2) of the CTNNBIP1 gene. This alteration results from a A to G substitution at nucleotide position 145, causing the asparagine (N) at amino acid position 49 to be replaced by an aspartic acid (D). 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	0.19
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	22
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.45	T;T;T;T
Eigen	Benign	-0.23
Eigen_PC	Benign	-0.099
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.83	.;.;.;T
M_CAP	Benign	0.0051	T
MetaRNN	Benign	0.25	T;T;T;T
MetaSVM	Benign	-0.96	T
PrimateAI	Benign	0.34	T
PROVEAN	Uncertain	-2.4	N;N;N;N
REVEL	Benign	0.084
Sift	Benign	0.16	T;T;T;T
Sift4G	Benign	0.18	T;T;T;T
Polyphen		0.0020	B;B;B;B
Vest4		0.24
MutPred		0.55		Gain of loop (P = 0.0851);Gain of loop (P = 0.0851);Gain of loop (P = 0.0851);Gain of loop (P = 0.0851);
MVP		0.28
MPC		0.37
ClinPred		0.87	D
GERP RS		3.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.23
gMVP		0.55

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: rs745668650; hg19: chr1-9931287;