11-57794071-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.257A>G(p.Asn86Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00108 in 1,613,996 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. N86N) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0010 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0011 (4 hom.)
• Consequence: CTNND1 NM_001085458.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 2.97

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=0.007977247).
• BP6: Variant 11-57794071-A-G is Benign according to our data. Variant chr11-57794071-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 722491.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-57794071-A-G is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00102 (155/152318) while in subpopulation AMR AF= 0.00268 (41/15304). AF 95% confidence interval is 0.00203. There are 0 homozygotes in gnomad4. There are 70 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 155 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CTNND1	NM_001085458.2	c.257A>G	p.Asn86Ser	missense_variant	4/21	ENST00000399050.10
TMX2-CTNND1	NR_037646.1	n.816A>G		non_coding_transcript_exon_variant	5/21

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CTNND1	ENST00000399050.10	c.257A>G	p.Asn86Ser	missense_variant	4/21	1	NM_001085458.2

Frequencies

GnomAD3 genomes AF: 0.00102 AC: 155 AN: 152200 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000338

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00268

Gnomad ASJ AF: 0.0115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000838

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.00122 AC: 301 AN: 246852 Hom.: 2 AF XY: 0.00119 AC XY: 160 AN XY: 134144

Gnomad AFR exome AF: 0.0000646

Gnomad AMR exome AF: 0.000666

Gnomad ASJ exome AF: 0.0129

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000196

Gnomad FIN exome AF: 0.0000928

Gnomad NFE exome AF: 0.00120

Gnomad OTH exome AF: 0.000993

GnomAD4 exome AF: 0.00109 AC: 1586 AN: 1461678 Hom.: 4 Cov.: 31 AF XY: 0.00109 AC XY: 791 AN XY: 727128

Gnomad4 AFR exome AF: 0.000299

Gnomad4 AMR exome AF: 0.000917

Gnomad4 ASJ exome AF: 0.0140

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000232

Gnomad4 FIN exome AF: 0.000112

Gnomad4 NFE exome AF: 0.000941

Gnomad4 OTH exome AF: 0.00157

GnomAD4 genome AF: 0.00102 AC: 155 AN: 152318 Hom.: 0 Cov.: 32 AF XY: 0.000940 AC XY: 70 AN XY: 74478

Gnomad4 AFR AF: 0.000337

Gnomad4 AMR AF: 0.00268

Gnomad4 ASJ AF: 0.0115

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000838

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00144 Hom.: 0

Bravo AF: 0.00127

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.000541 AC: 2

ESP6500EA AF: 0.00147 AC: 12

ExAC AF: 0.00104 AC: 126

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00109

EpiControl AF: 0.000652

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

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 -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Dec 31, 2019	- -

CTNND1-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 09, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.41
Cadd	Benign	20
Dann	Uncertain	1.0
Eigen	Benign	-0.099
Eigen_PC	Benign	0.034
FATHMM_MKL	Uncertain	0.83	D
M_CAP	Benign	0.029	D
MetaRNN	Benign	0.0080	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.57	T
MutationAssessor	Benign	0.76	N;.;N;.;N;N;N;N;.;.;.;N;.;.;.;.;N;.
MutationTaster	Benign	0.92	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	Benign	0.42	T
PROVEAN	Benign	-0.72	N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N
REVEL	Benign	0.072
Sift	Benign	0.036	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
Sift4G	Benign	0.43	T;T;T;D;T;T;T;T;D;D;D;T;D;D;D;D;T;T
Polyphen		0.011	B;B;P;.;P;.;P;B;.;.;.;B;.;.;D;.;.;.
Vest4		0.20
MVP		0.78
MPC		0.27
ClinPred		0.028	T
GERP RS		3.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.15
gMVP		0.41

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: rs76817459; hg19: chr11-57561543; COSMIC: COSV62382850; COSMIC: COSV62382850;