9-108943764-G-A

Position:

• chr9-108943764-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The ENST00000325551.9(CTNNAL1):​c.1994C>T​(p.Pro665Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,566 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: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: CTNNAL1 ENST00000325551.9 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.68

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]

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.26477355).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CTNNAL1	NM_003798.4	c.1994C>T	p.Pro665Leu	missense_variant	17/19	ENST00000325551.9	NP_003789.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CTNNAL1	ENST00000325551.9	c.1994C>T	p.Pro665Leu	missense_variant	17/19	1	NM_003798.4	ENSP00000320434	P1
CTNNAL1	ENST00000374595.8	c.1994C>T	p.Pro665Leu	missense_variant	17/19	1		ENSP00000363723
CTNNAL1	ENST00000374594.1	c.197C>T	p.Pro66Leu	missense_variant	6/8	3		ENSP00000363722
ABITRAM	ENST00000374624.7	c.262-6743G>A		intron_variant		3		ENSP00000363754

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461566 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727052

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 0.0000331

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 07, 2023

The c.1994C>T (p.P665L) alteration is located in exon 17 (coding exon 17) of the CTNNAL1 gene. This alteration results from a C to T substitution at nucleotide position 1994, causing the proline (P) at amino acid position 665 to be replaced by a leucine (L). 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	0.17
BayesDel_addAF	Uncertain	0.045	T
BayesDel_noAF	Benign	-0.17
CADD	Benign	22
DANN	Benign	0.97
DEOGEN2	Benign	0.022	.;T;.
Eigen	Benign	0.13
Eigen_PC	Uncertain	0.29
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.81	T;T;T
M_CAP	Benign	0.026	D
MetaRNN	Benign	0.26	T;T;T
MetaSVM	Benign	-0.71	T
MutationAssessor	Uncertain	2.3	M;M;.
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-2.0	N;N;D
REVEL	Benign	0.12
Sift	Benign	0.17	T;D;D
Sift4G	Uncertain	0.036	D;D;D
Polyphen		0.016	B;P;.
Vest4		0.30
MutPred		0.33		Gain of catalytic residue at P665 (P = 0.0466);Gain of catalytic residue at P665 (P = 0.0466);.;
MVP		0.71
MPC		0.41
ClinPred		0.97	D
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.14
gMVP		0.30

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1830316754; hg19: chr9-111706044;