rs1060502221

Variant names:

• chr5-138929255-G-A
• rs1060502221
• NM_001903.5:c.1909G>A

Your query was ambiguous. Multiple possible variants found:

• chr5-138929255-G-A
• chr5-138929255-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001903.5(CTNNA1):​c.1909G>A​(p.Glu637Lys) variant causes a missense change involving the alteration of a conserved nucleotide. 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 (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CTNNA1 NM_001903.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 10.0

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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.767

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CTNNA1	NM_001903.5	c.1909G>A	p.Glu637Lys	missense_variant	Exon 14 of 18	ENST00000302763.12	NP_001894.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CTNNA1	ENST00000302763.12	c.1909G>A	p.Glu637Lys	missense_variant	Exon 14 of 18	1	NM_001903.5	ENSP00000304669.7

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 27

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:1

Jun 26, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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: "Possibly Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals with CTNNA1-related conditions. ClinVar contains an entry for this variant (Variation ID: 409005). This variant is not present in population databases (ExAC no frequency). This sequence change replaces glutamic acid with lysine at codon 637 of the CTNNA1 protein (p.Glu637Lys). The glutamic acid residue is highly conserved and there is a small physicochemical difference between glutamic acid and lysine. -

Hereditary cancer-predisposing syndrome Uncertain:1

May 22, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.E637K variant (also known as c.1909G>A), located in coding exon 13 of the CTNNA1 gene, results from a G to A substitution at nucleotide position 1909. The glutamic acid at codon 637 is replaced by lysine, an amino acid with similar properties. In one study, this alteration was identified in 1/151,425 individuals who underwent multi-gene germline genetic testing and classified as a variant of uncertain significance by the authors (Clark DF et al. Genet Med, 2020 May;22:840-846). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.12
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.021	T;T;T;.
Eigen	Pathogenic	0.77
Eigen_PC	Pathogenic	0.80
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	0.98	D;D;.;D
M_CAP	Benign	0.034	D
MetaRNN	Pathogenic	0.77	D;D;D;D
MetaSVM	Benign	-0.87	T
MutationAssessor	Uncertain	2.6	.;M;.;.
PrimateAI	Pathogenic	0.93	D
PROVEAN	Uncertain	-2.5	.;D;N;D
REVEL	Uncertain	0.36
Sift	Uncertain	0.0040	.;D;D;D
Sift4G	Uncertain	0.010	D;D;D;D
Polyphen		0.99	D;P;D;.
Vest4		0.77
MutPred		0.56		Gain of ubiquitination at E637 (P = 0.0114);Gain of ubiquitination at E637 (P = 0.0114);Gain of ubiquitination at E637 (P = 0.0114);.;
MVP		0.81
MPC		2.0
ClinPred		0.99	D
GERP RS		5.5
Varity_R		0.68
gMVP		0.74

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: rs1060502221; hg19: chr5-138264944; COSMIC: COSV100243041; COSMIC: COSV100243041;