11-57794061-T-A

Position:

• chr11-57794061-T-A

Variant summary

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

The NM_001085463.2(CTNND1):​c.-57T>A variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,700 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: CTNND1 NM_001085463.2 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.17

Genes affected

CTNND1 (HGNC:2515): (catenin delta 1) This gene encodes a member of the Armadillo protein family, which function in adhesion between cells and signal transduction. Multiple translation initiation codons and alternative splicing result in many different isoforms being translated. Not all of the full-length natures of the described transcript variants have been determined. Read-through transcription also exists between this gene and the neighboring upstream thioredoxin-related transmembrane protein 2 (TMX2) gene. [provided by RefSeq, Dec 2010]

ENSG00000288534 (HGNC:):

TMX2-CTNND1 (HGNC:41992): (TMX2-CTNND1 readthrough (NMD candidate)) This locus represents naturally occurring read-through transcription between the neighboring TMX2 (thioredoxin-related transmembrane protein 2) and CTNND1 (catenin, cadherin-associated protein, delta 1) genes on chromosome 11. The read-through transcript is a candidate for nonsense-mediated mRNA decay (NMD), and is therefore unlikely to produce a protein product. [provided by RefSeq, Dec 2010]

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=0.19181368).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CTNND1	NM_001085458.2	c.247T>A	p.Leu83Met	missense_variant	4/21	ENST00000399050.10	NP_001078927.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CTNND1	ENST00000399050.10	c.247T>A	p.Leu83Met	missense_variant	4/21	1	NM_001085458.2	ENSP00000382004.5
ENSG00000288534	ENST00000674060.1	n.*398T>A		non_coding_transcript_exon_variant	5/20			ENSP00000501055.2
ENSG00000288534	ENST00000674060.1	n.*398T>A		3_prime_UTR_variant	5/20			ENSP00000501055.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461700 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727130

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 26, 2024

The c.247T>A (p.L83M) alteration is located in exon 4 (coding exon 2) of the CTNND1 gene. This alteration results from a T to A substitution at nucleotide position 247, causing the leucine (L) at amino acid position 83 to be replaced by a methionine (M). 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	0.10
BayesDel_addAF	Uncertain	0.032	T
BayesDel_noAF	Benign	-0.19
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.012	.;T;.;.;T;.;.;.;.;.;.;.;.;.;.;.;.;T
Eigen	Benign	-0.066
Eigen_PC	Benign	-0.020
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Uncertain	0.95	.;D;D;.;D;D;D;.;.;.;D;D;D;D;D;D;D;D
M_CAP	Benign	0.025	T
MetaRNN	Benign	0.19	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.68	T
MutationAssessor	Benign	1.4	L;.;L;.;L;L;L;L;.;.;.;L;.;.;.;.;L;.
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	-0.26	N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N
REVEL	Benign	0.18
Sift	Benign	0.21	T;T;T;D;T;T;T;T;D;D;D;T;T;D;D;D;T;T
Sift4G	Benign	0.11	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
Polyphen		0.13	B;D;D;.;D;.;D;B;.;.;.;B;.;.;D;.;.;.
Vest4		0.29
MutPred		0.19		Gain of methylation at K79 (P = 0.0665);Gain of methylation at K79 (P = 0.0665);Gain of methylation at K79 (P = 0.0665);.;Gain of methylation at K79 (P = 0.0665);Gain of methylation at K79 (P = 0.0665);Gain of methylation at K79 (P = 0.0665);Gain of methylation at K79 (P = 0.0665);.;.;.;Gain of methylation at K79 (P = 0.0665);.;.;.;.;Gain of methylation at K79 (P = 0.0665);.;
MVP		0.66
MPC		0.70
ClinPred		0.52	D
GERP RS		-0.050
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.13
gMVP		0.20

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: rs2061066542; hg19: chr11-57561533;