2-203380343-A-G

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_Moderate BP6 BS2

The NM_001375670.1(ABI2):c.421A>G(p.Ile141Val) variant causes a missense change. The variant allele was found at a frequency of 0.000672 in 1,598,598 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00052 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00069 (4 hom.)
• Consequence: ABI2 NM_001375670.1 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 5.37

Genes affected

ABI2 (HGNC:24011): (abl interactor 2) Enables several functions, including SH3 domain binding activity; identical protein binding activity; and ubiquitin protein ligase binding activity. Contributes to small GTPase binding activity. Involved in Rac protein signal transduction; positive regulation of cellular component organization; and zonula adherens assembly. Acts upstream of or within peptidyl-tyrosine phosphorylation. Located in several cellular components, including filopodium tip; lamellipodium; and nucleoplasm. Part of SCAR complex. Is active in adherens junction. Colocalizes with actin filament. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Benign. Variant got -7 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.09811735).
• BP6: Variant 2-203380343-A-G is Benign according to our data. Variant chr2-203380343-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 3045954.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=1}.
• BS2: High AC in GnomAd at 80 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ABI2	NM_001375670.1	c.421A>G	p.Ile141Val	missense_variant	3/12	ENST00000261018.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ABI2	ENST00000261018.12	c.421A>G	p.Ile141Val	missense_variant	3/12	1	NM_001375670.1

Frequencies

GnomAD3 genomes AF: 0.000526 AC: 80 AN: 152182 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000193

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000720

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000779

Gnomad OTH AF: 0.000956

GnomAD3 exomes AF: 0.000606 AC: 143 AN: 236150 Hom.: 0 AF XY: 0.000571 AC XY: 73 AN XY: 127736

Gnomad AFR exome AF: 0.0000643

Gnomad AMR exome AF: 0.000923

Gnomad ASJ exome AF: 0.00208

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000374

Gnomad FIN exome AF: 0.0000465

Gnomad NFE exome AF: 0.000785

Gnomad OTH exome AF: 0.00107

GnomAD4 exome AF: 0.000688 AC: 995 AN: 1446298 Hom.: 4 Cov.: 30 AF XY: 0.000688 AC XY: 495 AN XY: 719154

Gnomad4 AFR exome AF: 0.000123

Gnomad4 AMR exome AF: 0.000873

Gnomad4 ASJ exome AF: 0.00164

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000182

Gnomad4 FIN exome AF: 0.0000188

Gnomad4 NFE exome AF: 0.000754

Gnomad4 OTH exome AF: 0.000838

GnomAD4 genome AF: 0.000519 AC: 79 AN: 152300 Hom.: 0 Cov.: 33 AF XY: 0.000470 AC XY: 35 AN XY: 74484

Gnomad4 AFR AF: 0.000192

Gnomad4 AMR AF: 0.000719

Gnomad4 ASJ AF: 0.00144

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000779

Gnomad4 OTH AF: 0.000946

Alfa AF: 0.000975 Hom.: 1

Bravo AF: 0.000601

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000698 AC: 6

ExAC AF: 0.000519 AC: 63

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 12, 2021

The c.421A>G (p.I141V) alteration is located in exon 3 (coding exon 3) of the ABI2 gene. This alteration results from a A to G substitution at nucleotide position 421, causing the isoleucine (I) at amino acid position 141 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

ABI2-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 29, 2022

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.17
Cadd	Uncertain	25
Dann	Uncertain	0.99
DEOGEN2	Benign	0.18	T;T;.;.;T;T;T;.
Eigen	Uncertain	0.26
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Uncertain	0.94	D
M_CAP	Benign	0.058	D
MetaRNN	Benign	0.098	T;T;T;T;T;T;T;T
MetaSVM	Pathogenic	0.87	D
MutationTaster	Benign	1.0	D;D;D;D;D;D
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	-0.78	N;.;.;N;N;N;N;N
REVEL	Uncertain	0.49
Sift	Benign	0.031	D;.;.;D;D;D;D;D
Sift4G	Benign	0.12	T;T;T;T;T;T;T;T
Polyphen		1.0, 0.011	.;.;D;B;.;.;.;.
Vest4		0.20
MVP		0.76
MPC		0.56
ClinPred		0.051	T
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
gMVP		0.85

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: rs141392713; hg19: chr2-204245066;