4-25012345-G-T

Position:

• chr4-25012345-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_018176.4(LGI2):​c.810C>A​(p.Asp270Glu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: LGI2 NM_018176.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.99

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 2 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LGI2	NM_018176.4	c.810C>A	p.Asp270Glu	missense_variant	7/8	ENST00000382114.9	NP_060646.2
LGI2	XM_011513850.3	c.810C>A	p.Asp270Glu	missense_variant	7/8		XP_011512152.1
LGI2	XM_017008356.2	c.810C>A	p.Asp270Glu	missense_variant	7/8		XP_016863845.1
LOC102723675	XR_007058082.1	n.1049-12385G>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LGI2	ENST00000382114.9	c.810C>A	p.Asp270Glu	missense_variant	7/8	1	NM_018176.4	ENSP00000371548	P1
LGI2	ENST00000512108.1	c.627+5644C>A		intron_variant		2		ENSP00000426254

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

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

Jul 19, 2023

The c.810C>A (p.D270E) alteration is located in exon 7 (coding exon 7) of the LGI2 gene. This alteration results from a C to A substitution at nucleotide position 810, causing the aspartic acid (D) at amino acid position 270 to be replaced by a glutamic acid (E). 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	0.75
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.050
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.27	T
Eigen	Benign	0.043
Eigen_PC	Benign	0.18
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.86	D
M_CAP	Benign	0.056	D
MetaRNN	Uncertain	0.65	D
MetaSVM	Benign	-0.43	T
MutationAssessor	Benign	1.7	L
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.88	D
PROVEAN	Benign	-2.1	N
REVEL	Uncertain	0.47
Sift	Benign	0.25	T
Sift4G	Benign	0.26	T
Polyphen		0.30	B
Vest4		0.73
MutPred		0.48		Gain of disorder (P = 0.2251);
MVP		0.88
MPC		1.1
ClinPred		0.94	D
GERP RS		4.8
Varity_R		0.26
gMVP		0.35

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: rs1577551438; hg19: chr4-25013967;