rs75050399

Variant names:

• chr5-138932622-A-C
• rs75050399
• NM_001903.5:c.2343A>C

Your query was ambiguous. Multiple possible variants found:

• chr5-138932622-A-C
• chr5-138932622-A-G
• chr5-138932622-A-T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 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
• Publications: 2 publications found

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]

CTNNA1 Gene-Disease associations (from GenCC):

• CTNNA1-related diffuse gastric and lobular breast cancer syndrome

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• patterned macular dystrophy 2

  Inheritance: AD Classification: DEFINITIVE, STRONG, LIMITED Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
• patterned macular dystrophy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• hereditary nonpolyposis colon cancer

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.821

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001903.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CTNNA1	NM_001903.5	MANE Select	c.2343A>C	p.Gln781His	missense	Exon 17 of 18	NP_001894.2
	CTNNA1	NM_001323982.2		c.2343A>C	p.Gln781His	missense	Exon 18 of 19	NP_001310911.1
	CTNNA1	NM_001323983.1		c.2343A>C	p.Gln781His	missense	Exon 17 of 18	NP_001310912.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CTNNA1	ENST00000302763.12	TSL:1 MANE Select	c.2343A>C	p.Gln781His	missense	Exon 17 of 18	ENSP00000304669.7
	CTNNA1	ENST00000518825.5	TSL:1	c.2343A>C	p.Gln781His	missense	Exon 16 of 18	ENSP00000427821.1
	CTNNA1	ENST00000540387.5	TSL:1	c.1233A>C	p.Gln411His	missense	Exon 11 of 12	ENSP00000438476.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Benign	0.090
Eigen_PC	Benign	0.058
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.77	T
M_CAP	Benign	0.047	D
MetaRNN	Pathogenic	0.82	D
MetaSVM	Benign	-0.67	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		3.7
PrimateAI	Pathogenic	0.88	D
PROVEAN	Uncertain	-3.0	D
REVEL	Uncertain	0.42
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.0060	D
Polyphen		0.97	D
Vest4		0.83
MutPred		0.59		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
Mutation Taster		=70/30	polymorphism

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

Other links and lift over

dbSNP: rs75050399; hg19: chr5-138268311;