2-152578956-G-T

Position:

• chr2-152578956-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP2

The NM_052905.4(FMNL2):​c.774G>T​(p.Lys258Asn) variant causes a missense change involving the alteration of a non-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: 1.49

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

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, FMNL2

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FMNL2	NM_052905.4	c.774G>T	p.Lys258Asn	missense_variant	8/26	ENST00000288670.14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FMNL2	ENST00000288670.14	c.774G>T	p.Lys258Asn	missense_variant	8/26	1	NM_052905.4	P1
FMNL2	ENST00000475377.3	c.774G>T	p.Lys258Asn	missense_variant	8/28	5
FMNL2	ENST00000492942.1	n.336G>T		non_coding_transcript_exon_variant	1/3	3

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

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 30, 2022

The c.774G>T (p.K258N) alteration is located in exon 8 (coding exon 8) of the FMNL2 gene. This alteration results from a G to T substitution at nucleotide position 774, causing the lysine (K) at amino acid position 258 to be replaced by an asparagine (N). 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	0.024	T
BayesDel_noAF	Benign	-0.20
CADD	Uncertain	25
DANN	Uncertain	1.0
Eigen	Uncertain	0.29
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.89	D
M_CAP	Benign	0.082	D
MetaRNN	Uncertain	0.52	D
MetaSVM	Uncertain	0.13	D
MutationAssessor	Benign	0.70	N
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.87	D
PROVEAN	Uncertain	-3.8	D
REVEL	Uncertain	0.57
Sift	Benign	0.070	T
Sift4G	Benign	0.12	T
Polyphen		1.0	D
Vest4		0.57
MutPred		0.49		Loss of ubiquitination at K258 (P = 0.0174);
MVP		0.67
MPC		0.47
ClinPred		0.96	D
GERP RS		2.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
gMVP		0.50

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: rs952649959; hg19: chr2-153435470;