Genetic Variant CTNNAL1:p.Asp687Asn (chr9-108943041-C-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_003798.4(CTNNAL1):c.2059G>A(p.Asp687Asn) variant causes a missense change. The variant allele was found at a frequency of 0.0000946 in 1,607,324 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00046 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000056 ( 0 hom. )

Consequence

CTNNAL1
NM_003798.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.52

Variant links:

Genes affected

CTNNAL1 (HGNC:2512): (catenin alpha like 1) Predicted to enable actin filament binding activity and cadherin binding activity. Acts upstream of or within Rho protein signal transduction. Located in cytosol. [provided by Alliance of Genome Resources, Apr 2022]

CTNNAL1 links:

ABITRAM (HGNC:1364): (actin binding transcription modulator) Predicted to enable actin filament binding activity and actin monomer binding activity. Predicted to be involved in dendrite morphogenesis; regulation of actin filament polymerization; and regulation of filopodium assembly. Predicted to be located in growth cone. Predicted to be active in several cellular components, including dendrite; filopodium tip; and lamellipodium. [provided by Alliance of Genome Resources, Apr 2022]

ABITRAM links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.04319021).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CTNNAL1	NM_003798.4 link	c.2059G>A	p.Asp687Asn	missense_variant	Exon 18 of 19	ENST00000325551.9	NP_003789.1	Q9UBT7-1B3KMX6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
CTNNAL1	ENST00000325551.9 link	c.2059G>A	p.Asp687Asn	missense_variant	Exon 18 of 19	1	NM_003798.4	ENSP00000320434.4	Q9UBT7-1
CTNNAL1	ENST00000374595.8 link	c.2059G>A	p.Asp687Asn	missense_variant	Exon 18 of 19	1		ENSP00000363723.4	Q9UBT7-2
CTNNAL1	ENST00000374594.1 link	c.262G>A	p.Asp88Asn	missense_variant	Exon 7 of 8	3		ENSP00000363722.1	Q5JTQ9
ABITRAM	ENST00000374624.7 link	c.261+6604C>T		intron_variant	Intron 3 of 3	3		ENSP00000363754.3	X6R8U7

Frequencies

GnomAD3 genomes

AF:

0.000467

AC:

AN:

152174

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00159

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000139

AC:

AN:

245416

Hom.:

AF XY:

0.0000680

AC XY:

AN XY:

132378

show subpopulations

Gnomad AFR exome

AF:

0.00205

Gnomad AMR exome

AF:

0.0000299

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000564

AC:

AN:

1455032

Hom.:

Cov.:

AF XY:

0.0000415

AC XY:

AN XY:

723282

show subpopulations

Gnomad4 AFR exome

AF:

0.00193

Gnomad4 AMR exome

AF:

0.0000230

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000540

Gnomad4 OTH exome

AF:

0.000167

GnomAD4 genome

AF:

0.000460

AC:

AN:

152292

Hom.:

Cov.:

AF XY:

0.000416

AC XY:

AN XY:

74474

show subpopulations

Gnomad4 AFR

AF:

0.00159

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.000144

Hom.:

Bravo

AF:

0.000578

ESP6500AA

AF:

0.00182

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000157

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Feb 18, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2059G>A (p.D687N) alteration is located in exon 18 (coding exon 18) of the CTNNAL1 gene. This alteration results from a G to A substitution at nucleotide position 2059, causing the aspartic acid (D) at amino acid position 687 to be replaced by an asparagine (N). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.36

BayesDel_noAF

Benign

-0.29

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.32

.;T;.

Eigen

Pathogenic

0.85

Eigen_PC

Pathogenic

0.84

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.91

D;D;D

M_CAP

Benign

0.053

MetaRNN

Benign

0.043

T;T;T

MetaSVM

Benign

-0.42

MutationAssessor

Uncertain

2.5

M;M;.

PrimateAI

Uncertain

0.49

PROVEAN

Uncertain

-3.8

D;D;D

REVEL

Uncertain

0.42

Sift

Uncertain

0.023

D;D;D

Sift4G

Uncertain

0.030

D;D;D

Polyphen

1.0

D;D;.

Vest4

0.58

MVP

0.81

MPC

0.57

ClinPred

0.18

GERP RS

5.8

Varity_R

0.45

gMVP

0.37

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over