11-57795716-G-A

Variant summary

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

The NM_001085458.2(CTNND1):c.407G>A(p.Arg136His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000152 in 1,444,898 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R136C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.000015 (0 hom.)
• Consequence: CTNND1 NM_001085458.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.60

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]

TMX2-CTNND1 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CTNND1	NM_001085458.2	c.407G>A	p.Arg136His	missense_variant	5/21	ENST00000399050.10
TMX2-CTNND1	NR_037646.1	n.966G>A		non_coding_transcript_exon_variant	6/21

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CTNND1	ENST00000399050.10	c.407G>A	p.Arg136His	missense_variant	5/21	1	NM_001085458.2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.0000152 AC: 22 AN: 1444898 Hom.: 0 Cov.: 31 AF XY: 0.0000125 AC XY: 9 AN XY: 718452

Gnomad4 AFR exome AF: 0.0000309

Gnomad4 AMR exome AF: 0.0000503

Gnomad4 ASJ exome AF: 0.0000394

Gnomad4 EAS exome AF: 0.0000254

Gnomad4 SAS exome AF: 0.0000120

Gnomad4 FIN exome AF: 0.0000190

Gnomad4 NFE exome AF: 0.0000117

Gnomad4 OTH exome AF: 0.0000335

GnomAD4 genome Cov.: 31

Bravo AF: 0.00000378

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

Mar 06, 2023

The c.407G>A (p.R136H) alteration is located in exon 5 (coding exon 3) of the CTNND1 gene. This alteration results from a G to A substitution at nucleotide position 407, causing the arginine (R) at amino acid position 136 to be replaced by a histidine (H). 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	0.71
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.15
Cadd	Pathogenic	33
Dann	Pathogenic	1.0
Eigen	Pathogenic	0.86
Eigen_PC	Pathogenic	0.87
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Uncertain	0.20	D
MetaRNN	Uncertain	0.65	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.42	D
MutationAssessor	Uncertain	2.3	M;.;M;.;.;M;M;M;.;.;M;.;.;.;.;M;.;.;.;.;.;.;.;.;M;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
PrimateAI	Pathogenic	0.87	D
PROVEAN	Benign	-1.8	N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;D;D
REVEL	Uncertain	0.34
Sift	Uncertain	0.0030	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
Sift4G	Benign	0.11	T;T;T;D;D;T;T;T;D;D;T;D;D;D;D;T;D;D;D;D;D;D;D;D;T;D;D
Polyphen		1.0	D;D;D;.;.;D;.;D;.;.;D;.;.;.;.;D;.;D;.;D;.;.;.;.;.;.;.
Vest4		0.71
MutPred		0.45		Loss of MoRF binding (P = 0.0371);Loss of MoRF binding (P = 0.0371);Loss of MoRF binding (P = 0.0371);.;.;Loss of MoRF binding (P = 0.0371);Loss of MoRF binding (P = 0.0371);Loss of MoRF binding (P = 0.0371);.;.;Loss of MoRF binding (P = 0.0371);.;.;.;.;Loss of MoRF binding (P = 0.0371);.;.;.;.;.;.;.;.;Loss of MoRF binding (P = 0.0371);.;.;
MVP		0.88
MPC		1.2
ClinPred		0.61	D
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.18
gMVP		0.60

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: rs867108561; hg19: chr11-57563188; COSMIC: COSV62382919; COSMIC: COSV62382919;