rs75050399

chr5-138932622-A-Cchr5-138932622-A-Gchr5-138932622-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP2 PP3

The NM_001903.5(CTNNA1):c.2343A>C(p.Gln781His) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 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. Q781E) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CTNNA1 NM_001903.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.69

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 Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, CTNNA1
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.821

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CTNNA1	NM_001903.5	c.2343A>C	p.Gln781His	missense_variant	17/18	ENST00000302763.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CTNNA1	ENST00000302763.12	c.2343A>C	p.Gln781His	missense_variant	17/18	1	NM_001903.5	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

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

Invitae

Oct 20, 2020

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals with CTNNA1-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change replaces glutamine with histidine at codon 781 of the CTNNA1 protein (p.Gln781His). The glutamine residue is highly conserved and there is a small physicochemical difference between glutamine and histidine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.82
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.080
Cadd	Benign	23
Dann	Uncertain	0.99
DEOGEN2	Benign	0.15	T;D;T;.
Eigen	Benign	0.090
Eigen_PC	Benign	0.058
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.77	T;T;.;T
M_CAP	Benign	0.047	D
MetaRNN	Pathogenic	0.82	D;D;D;D
MetaSVM	Benign	-0.67	T
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Pathogenic	0.88	D
Sift4G	Uncertain	0.0060	D;D;D;D
Polyphen		0.97	D;P;D;.
Vest4		0.83
MutPred		0.59		Loss of catalytic residue at Q781 (P = 0.0022);Loss of catalytic residue at Q781 (P = 0.0022);Loss of catalytic residue at Q781 (P = 0.0022);.;
MVP		0.83
MPC		2.0
ClinPred		0.97	D
GERP RS		2.8
Varity_R		0.81
gMVP		0.80

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: rs75050399; hg19: chr5-138268311;