11-57794013-G-C

Position:

• chr11-57794013-G-C

Variant summary

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

The NM_001085458.2(CTNND1):​c.199G>C​(p.Gly67Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,672 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. G67D) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: CTNND1 NM_001085458.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.40

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CTNND1	NM_001085458.2	c.199G>C	p.Gly67Arg	missense_variant	4/21	ENST00000399050.10
TMX2-CTNND1	NR_037646.1	n.758G>C		non_coding_transcript_exon_variant	5/21

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CTNND1	ENST00000399050.10	c.199G>C	p.Gly67Arg	missense_variant	4/21	1	NM_001085458.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461672 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727124

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: 8.99e-7

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

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

Apr 12, 2022

The c.199G>C (p.G67R) alteration is located in exon 4 (coding exon 2) of the CTNND1 gene. This alteration results from a G to C substitution at nucleotide position 199, causing the glycine (G) at amino acid position 67 to be replaced by an arginine (R). 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	0.90
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.31
CADD	Uncertain	25
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.035	.;T;.;.;T;.;.;.;.;.;.;.;.;.;.;.;.;T
Eigen	Uncertain	0.68
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	0.98	.;D;D;.;D;D;D;.;.;.;D;D;D;D;D;D;D;D
M_CAP	Uncertain	0.098	D
MetaRNN	Uncertain	0.71	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.15	D
MutationAssessor	Benign	1.7	L;.;L;.;L;L;L;L;.;.;.;L;.;.;.;.;L;.
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	Uncertain	0.78	T
PROVEAN	Benign	-1.8	N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;D
REVEL	Uncertain	0.41
Sift	Uncertain	0.0020	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
Sift4G	Benign	0.14	T;T;T;D;T;T;T;T;D;D;D;T;D;D;D;D;T;D
Polyphen		1.0	D;D;D;.;D;.;D;D;.;.;.;D;.;.;D;.;.;.
Vest4		0.61
MutPred		0.45		Gain of loop (P = 3e-04);Gain of loop (P = 3e-04);Gain of loop (P = 3e-04);.;Gain of loop (P = 3e-04);Gain of loop (P = 3e-04);Gain of loop (P = 3e-04);Gain of loop (P = 3e-04);.;.;.;Gain of loop (P = 3e-04);.;.;.;.;Gain of loop (P = 3e-04);.;
MVP		0.92
MPC		1.2
ClinPred		0.86	D
GERP RS		6.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.25
gMVP		0.56

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: rs920179547; hg19: chr11-57561485;