Genetic Variant CTNNAL1:p.Gln642Arg (chr9-108943978-T-C) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_003798.4(CTNNAL1):c.1925A>G(p.Gln642Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,514 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

CTNNAL1
NM_003798.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.32

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:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.16434523).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CTNNAL1	NM_003798.4 link	c.1925A>G	p.Gln642Arg	missense_variant	Exon 16 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.1925A>G	p.Gln642Arg	missense_variant	Exon 16 of 19	1	NM_003798.4	ENSP00000320434.4	Q9UBT7-1
CTNNAL1	ENST00000374595.8 link	c.1925A>G	p.Gln642Arg	missense_variant	Exon 16 of 19	1		ENSP00000363723.4	Q9UBT7-2
CTNNAL1	ENST00000374594.1 link	c.128A>G	p.Gln43Arg	missense_variant	Exon 5 of 8	3		ENSP00000363722.1	Q5JTQ9
ABITRAM	ENST00000374624.7 link	c.262-6529T>C		intron_variant	Intron 3 of 3	3		ENSP00000363754.3	X6R8U7

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251080

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135710

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000290

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:

0.00000137

AC:

AN:

1461514

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727020

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000448

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:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Oct 09, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1925A>G (p.Q642R) alteration is located in exon 16 (coding exon 16) of the CTNNAL1 gene. This alteration results from a A to G substitution at nucleotide position 1925, causing the glutamine (Q) at amino acid position 642 to be replaced by an arginine (R). 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

0.084

BayesDel_addAF

Benign

-0.062

BayesDel_noAF

Benign

-0.33

CADD

Benign

DANN

Benign

0.89

DEOGEN2

Benign

0.012

.;T;.

Eigen

Benign

-0.29

Eigen_PC

Benign

-0.086

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Benign

0.80

T;T;T

M_CAP

Benign

0.014

MetaRNN

Benign

0.16

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.40

N;N;.

PrimateAI

Benign

0.39

PROVEAN

Benign

1.7

N;N;N

REVEL

Benign

0.18

Sift

Benign

1.0

T;T;T

Sift4G

Benign

1.0

T;T;T

Polyphen

0.0

B;B;.

Vest4

0.31

MutPred

0.51

Loss of ubiquitination at K646 (P = 0.0331);Loss of ubiquitination at K646 (P = 0.0331);.;

MVP

0.48

MPC

0.13

ClinPred

0.64

GERP RS

5.7

Varity_R

0.082

gMVP

0.11

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