11-57791633-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001085458.2(CTNND1):c.155A>G(p.Asn52Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0046 in 1,597,556 control chromosomes in the GnomAD database, including 27 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0031 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0048 (25 hom.)
• Consequence: CTNND1 NM_001085458.2 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.48

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0042743087).
• BP6: Variant 11-57791633-A-G is Benign according to our data. Variant chr11-57791633-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 717097.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00307 (467/152278) while in subpopulation NFE AF= 0.00556 (378/68018). AF 95% confidence interval is 0.0051. There are 2 homozygotes in gnomad4. There are 219 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 467 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CTNND1	NM_001085458.2	c.155A>G	p.Asn52Ser	missense_variant	3/21	ENST00000399050.10
TMX2-CTNND1	NR_037646.1	n.714A>G		non_coding_transcript_exon_variant	4/21

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CTNND1	ENST00000399050.10	c.155A>G	p.Asn52Ser	missense_variant	3/21	1	NM_001085458.2

Frequencies

GnomAD3 genomes AF: 0.00307 AC: 467 AN: 152160 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000893

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00190

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00141

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00556

Gnomad OTH AF: 0.000956

GnomAD3 exomes AF: 0.00301 AC: 707 AN: 234636 Hom.: 3 AF XY: 0.00313 AC XY: 399 AN XY: 127646

Gnomad AFR exome AF: 0.000735

Gnomad AMR exome AF: 0.000378

Gnomad ASJ exome AF: 0.00126

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00156

Gnomad NFE exome AF: 0.00591

Gnomad OTH exome AF: 0.00249

GnomAD4 exome AF: 0.00476 AC: 6881 AN: 1445278 Hom.: 25 Cov.: 30 AF XY: 0.00461 AC XY: 3312 AN XY: 717668

Gnomad4 AFR exome AF: 0.000639

Gnomad4 AMR exome AF: 0.000678

Gnomad4 ASJ exome AF: 0.00172

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000237

Gnomad4 FIN exome AF: 0.00224

Gnomad4 NFE exome AF: 0.00587

Gnomad4 OTH exome AF: 0.00330

GnomAD4 genome AF: 0.00307 AC: 467 AN: 152278 Hom.: 2 Cov.: 32 AF XY: 0.00294 AC XY: 219 AN XY: 74460

Gnomad4 AFR AF: 0.000891

Gnomad4 AMR AF: 0.00189

Gnomad4 ASJ AF: 0.00173

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00141

Gnomad4 NFE AF: 0.00556

Gnomad4 OTH AF: 0.000946

Alfa AF: 0.00454 Hom.: 5

Bravo AF: 0.00306

TwinsUK AF: 0.00378 AC: 14

ALSPAC AF: 0.00623 AC: 24

ESP6500AA AF: 0.000945 AC: 4

ESP6500EA AF: 0.00343 AC: 29

ExAC AF: 0.00334 AC: 404

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2023	CTNND1: BP4, BS2 -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Dec 31, 2019	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.055
BayesDel_addAF	Benign	-0.65	T
BayesDel_noAF	Benign	-0.70
Cadd	Benign	16
Dann	Benign	0.84
Eigen	Benign	-0.45
Eigen_PC	Benign	-0.24
FATHMM_MKL	Benign	0.52	D
M_CAP	Benign	0.0054	T
MetaRNN	Benign	0.0043	T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-1.1	N;.;N;N;N;N;N;N;N
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;N;N;N;N;N;N;N;N;N;N;N
PrimateAI	Benign	0.38	T
PROVEAN	Benign	0.47	N;N;N;N;N;N;N;N;N
REVEL	Benign	0.027
Sift	Benign	0.49	T;T;T;T;T;T;T;T;T
Sift4G	Benign	1.0	T;T;T;T;T;T;T;T;T
Polyphen		0.0	B;B;B;B;.;B;B;B;.
Vest4		0.13
MVP		0.43
MPC		0.27
ClinPred		0.0075	T
GERP RS		3.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.049
gMVP		0.33

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: rs145191455; hg19: chr11-57559105; COSMIC: COSV62384686; COSMIC: COSV62384686;