2-203395693-C-G

Variant names:

• chr2-203395693-C-G
• rs778466632
• NM_001375670.1:c.763C>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001375670.1(ABI2):​c.763C>G​(p.Arg255Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R255W) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 31)
• Consequence: ABI2 NM_001375670.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.76
• Publications: 1 publications found

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]

RAPH1 (HGNC:14436): (Ras association (RalGDS/AF-6) and pleckstrin homology domains 1) This gene encodes a protein that belongs to the Mig10/Rap1-interacting adaptor molecule/Lamellipodin family of adapter proteins, which function in cell migration. Members of this family contain pleckstrin-homology domains, Ras-association domains, and proline-rich C-termini. The protein encoded by this gene regulates actin dynamics through interaction with Ena/Vasodilator proteins as well as direct binding to filamentous actin to regulate actin network assembly. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2016]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.11475119).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001375670.1. 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
	ABI2	NM_001375670.1	MANE Select	c.763C>G	p.Arg255Gly	missense	Exon 7 of 12	NP_001362599.1	F8WAL6
	ABI2	NM_001375671.1		c.760C>G	p.Arg254Gly	missense	Exon 7 of 12	NP_001362600.1
	ABI2	NM_001375672.1		c.763C>G	p.Arg255Gly	missense	Exon 7 of 13	NP_001362601.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ABI2	ENST00000261018.12	TSL:1 MANE Select	c.763C>G	p.Arg255Gly	missense	Exon 7 of 12	ENSP00000261018.9	F8WAL6
	ABI2	ENST00000295851.10	TSL:1	c.763C>G	p.Arg255Gly	missense	Exon 7 of 11	ENSP00000295851.4	A0A7D9NKC8
	ABI2	ENST00000417864.5	TSL:1	c.763C>G	p.Arg255Gly	missense	Exon 7 of 11	ENSP00000414703.1	E7EP65

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 31

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.43
BayesDel_addAF	Benign	-0.069	T
BayesDel_noAF	Benign	-0.34
CADD	Uncertain	24
DANN	Uncertain	0.98
DEOGEN2	Benign	0.27	T
Eigen	Benign	-0.13
Eigen_PC	Benign	0.079
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.87	D
M_CAP	Benign	0.0088	T
MetaRNN	Benign	0.11	T
MetaSVM	Benign	-1.0	T
PhyloP100		2.8
PrimateAI	Uncertain	0.72	T
PROVEAN	Uncertain	-2.8	D
REVEL	Benign	0.13
Sift	Benign	0.80	T
Sift4G	Benign	0.43	T
Polyphen		0.0010	B
Vest4		0.48
MutPred		0.27		Loss of MoRF binding (P = 0.0156)
MVP		0.42
MPC		0.87
ClinPred		0.44	T
GERP RS		5.8
gMVP		0.55
Mutation Taster		=25/75	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.18		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: rs778466632; hg19: chr2-204260416;