2-152578903-G-A

Variant names:

• chr2-152578903-G-A
• NM_052905.4:c.721G>A

Variant summary

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

The NM_052905.4(FMNL2):​c.721G>A​(p.Val241Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: FMNL2 NM_052905.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.99
• Publications: 0 publications found

Genes affected

FMNL2 (HGNC:18267): (formin like 2) This gene encodes a formin-related protein. Formin-related proteins have been implicated in morphogenesis, cytokinesis, and cell polarity. Alternatively spliced transcript variants encoding different isoforms have been described but their full-length nature has yet to be determined. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FMNL2	NM_052905.4	c.721G>A	p.Val241Ile	missense_variant	Exon 8 of 26	ENST00000288670.14	NP_443137.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FMNL2	ENST00000288670.14	c.721G>A	p.Val241Ile	missense_variant	Exon 8 of 26	1	NM_052905.4	ENSP00000288670.9

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 12, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.721G>A (p.V241I) alteration is located in exon 8 (coding exon 8) of the FMNL2 gene. This alteration results from a G to A substitution at nucleotide position 721, causing the valine (V) at amino acid position 241 to be replaced by an isoleucine (I). 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
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.030
CADD	Uncertain	26
DANN	Uncertain	1.0
Eigen	Uncertain	0.52
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Benign	0.080	D
MetaRNN	Uncertain	0.53	D
MetaSVM	Uncertain	0.16	D
MutationAssessor	Benign	1.7	L
PhyloP100		10
PrimateAI	Pathogenic	0.85	D
PROVEAN	Benign	-0.92	N
REVEL	Uncertain	0.47
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.086	T
Polyphen		0.69	P
Vest4		0.45
MutPred		0.83		Loss of catalytic residue at V241 (P = 0.0597);
MVP		0.61
MPC		0.78
ClinPred		0.96	D
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
gMVP		0.43
Mutation Taster		=45/55	disease causing

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

Other links and lift over

hg19: chr2-153435417; COSMIC: COSV56495217;