11-57791626-G-C

Position:

• chr11-57791626-G-C

Variant summary

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

The NM_001085458.2(CTNND1):​c.148G>C​(p.Asp50His) variant causes a missense change. The variant allele was found at a frequency of 0.00000138 in 1,450,156 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar 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: 5.12

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.148G>C	p.Asp50His	missense_variant	3/21	ENST00000399050.10
TMX2-CTNND1	NR_037646.1	n.707G>C		non_coding_transcript_exon_variant	4/21

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CTNND1	ENST00000399050.10	c.148G>C	p.Asp50His	missense_variant	3/21	1	NM_001085458.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000138 AC: 2 AN: 1450156 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 720652

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: 0.00000181

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000936 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Sep 04, 2019

Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.41
BayesDel_addAF	Benign	-0.085	T
BayesDel_noAF	Benign	-0.36
CADD	Pathogenic	31
DANN	Uncertain	0.99
Eigen	Uncertain	0.45
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Uncertain	0.79	D
M_CAP	Benign	0.011	T
MetaRNN	Uncertain	0.45	T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	1.1	L;.;L;L;L;L;L;L;L
MutationTaster	Benign	0.96	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	0.68	T
PROVEAN	Benign	-0.72	N;N;N;N;N;N;N;N;N
REVEL	Benign	0.14
Sift	Benign	0.036	D;D;D;D;D;D;D;D;D
Sift4G	Benign	0.10	T;T;T;T;T;T;T;T;T
Polyphen		0.87	P;D;D;D;.;D;P;P;.
Vest4		0.64
MutPred		0.13		Gain of MoRF binding (P = 0.0432);Gain of MoRF binding (P = 0.0432);Gain of MoRF binding (P = 0.0432);Gain of MoRF binding (P = 0.0432);Gain of MoRF binding (P = 0.0432);Gain of MoRF binding (P = 0.0432);Gain of MoRF binding (P = 0.0432);Gain of MoRF binding (P = 0.0432);Gain of MoRF binding (P = 0.0432);
MVP		0.36
MPC		0.79
ClinPred		0.66	D
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.20
gMVP		0.70

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: rs2060756768; hg19: chr11-57559098;