4-25003957-A-T

Position:

• chr4-25003957-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_018176.4(LGI2):​c.1132T>A​(p.Phe378Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: LGI2 NM_018176.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.32

Genes affected

LGI2 (HGNC:18710): (leucine rich repeat LGI family member 2) Predicted to be involved in inhibitory synapse assembly. Predicted to be located in extracellular region. [provided by Alliance of Genome Resources, Apr 2022]

LOC102723675 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.763

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LGI2	NM_018176.4	c.1132T>A	p.Phe378Ile	missense_variant	8/8	ENST00000382114.9	NP_060646.2
LOC102723675	XR_001741618.3	n.8343A>T		non_coding_transcript_exon_variant	4/4
LGI2	XM_017008356.2	c.820+8378T>A		intron_variant			XP_016863845.1
LOC102723675	XR_007058082.1	n.1048+7416A>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LGI2	ENST00000382114.9	c.1132T>A	p.Phe378Ile	missense_variant	8/8	1	NM_018176.4	ENSP00000371548	P1
LGI2	ENST00000512108.1	c.628-4051T>A		intron_variant		2		ENSP00000426254

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

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

May 08, 2023

The c.1132T>A (p.F378I) alteration is located in exon 8 (coding exon 8) of the LGI2 gene. This alteration results from a T to A substitution at nucleotide position 1132, causing the phenylalanine (F) at amino acid position 378 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
AlphaMissense	Pathogenic	0.67
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.050
CADD	Pathogenic	28
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.62	D
Eigen	Uncertain	0.66
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.76	T
M_CAP	Uncertain	0.13	D
MetaRNN	Pathogenic	0.76	D
MetaSVM	Uncertain	0.30	D
MutationAssessor	Uncertain	2.0	M
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.87	D
PROVEAN	Uncertain	-3.9	D
REVEL	Pathogenic	0.72
Sift	Uncertain	0.016	D
Sift4G	Benign	0.086	T
Polyphen		0.99	D
Vest4		0.55
MutPred		0.61		Gain of glycosylation at T374 (P = 0.0581);
MVP		0.93
MPC		0.85
ClinPred		0.96	D
GERP RS		5.8
Varity_R		0.43
gMVP		0.66

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr4-25005579;