rs28363394

chr5-138812250-C-T

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 1P and 16B. PP2 BP4_Strong BP6_Very_Strong BS2

The NM_001903.5(CTNNA1):c.536C>T(p.Ala179Val) variant causes a missense change. The variant allele was found at a frequency of 0.00202 in 1,613,660 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A179T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0015 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0021 (2 hom.)
• Consequence: CTNNA1 NM_001903.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 4.02

Genes affected

CTNNA1 (HGNC:2509): (catenin alpha 1) This gene encodes a member of the catenin family of proteins that play an important role in cell adhesion process by connecting cadherins located on the plasma membrane to the actin filaments inside the cell. The encoded mechanosensing protein contains three vinculin homology domains and undergoes conformational changes in response to cytoskeletal tension, resulting in the reconfiguration of cadherin-actin filament connections. Certain mutations in this gene cause butterfly-shaped pigment dystrophy. [provided by RefSeq, May 2016]

ACMG classification

Verdict is Benign. Variant got -15 ACMG points.

• PP2: Missense variant where missense usually causes diseases, CTNNA1
• BP4: Computational evidence support a benign effect (MetaRNN=0.022231042).
• BP6: Variant 5-138812250-C-T is Benign according to our data. Variant chr5-138812250-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 415353.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-138812250-C-T is described in Lovd as [Likely_benign].
• BS2: High AC in GnomAd at 222 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CTNNA1	NM_001903.5	c.536C>T	p.Ala179Val	missense_variant	5/18	ENST00000302763.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CTNNA1	ENST00000302763.12	c.536C>T	p.Ala179Val	missense_variant	5/18	1	NM_001903.5	P1

Frequencies

GnomAD3 genomes AF: 0.00146 AC: 222 AN: 152008 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00118

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00104

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00266

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.00117 AC: 294 AN: 251350 Hom.: 0 AF XY: 0.00120 AC XY: 163 AN XY: 135832

Gnomad AFR exome AF: 0.000369

Gnomad AMR exome AF: 0.000376

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000458

Gnomad FIN exome AF: 0.00106

Gnomad NFE exome AF: 0.00202

Gnomad OTH exome AF: 0.00114

GnomAD4 exome AF: 0.00208 AC: 3038 AN: 1461534 Hom.: 2 Cov.: 30 AF XY: 0.00206 AC XY: 1501 AN XY: 727080

Gnomad4 AFR exome AF: 0.000299

Gnomad4 AMR exome AF: 0.000358

Gnomad4 ASJ exome AF: 0.0000766

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000371

Gnomad4 FIN exome AF: 0.00110

Gnomad4 NFE exome AF: 0.00256

Gnomad4 OTH exome AF: 0.00126

GnomAD4 genome AF: 0.00146 AC: 222 AN: 152126 Hom.: 1 Cov.: 32 AF XY: 0.00134 AC XY: 100 AN XY: 74376

Gnomad4 AFR AF: 0.000241

Gnomad4 AMR AF: 0.00118

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.00104

Gnomad4 NFE AF: 0.00266

Gnomad4 OTH AF: 0.000474

Alfa AF: 0.00251 Hom.: 1

Bravo AF: 0.00150

TwinsUK AF: 0.00189 AC: 7

ALSPAC AF: 0.00156 AC: 6

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00244 AC: 21

ExAC AF: 0.00118 AC: 143

EpiCase AF: 0.00240

EpiControl AF: 0.00243

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:5

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2022	CTNNA1: BS1, BS2 -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Jun 17, 2021

- -

CTNNA1-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 23, 2019

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

Hereditary cancer-predisposing syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 26, 2019

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.21
Cadd	Benign	21
Dann	Uncertain	0.99
DEOGEN2	Benign	0.022	T;T;T;.;T
Eigen	Benign	0.0017
Eigen_PC	Benign	0.20
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.96	D;D;D;D;.
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.022	T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.74	T
Sift4G	Benign	0.28	T;T;T;T;T
Polyphen		0.011	B;B;.;.;B
Vest4		0.42
MVP		0.57
MPC		0.13
ClinPred		0.018	T
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.22
gMVP		0.27

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: rs28363394; hg19: chr5-138147939;