10-93758208-T-A

Variant names:

• chr10-93758208-T-A
• NM_005097.4:c.64T>A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_005097.4(LGI1):​c.64T>A​(p.Phe22Ile) 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. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: LGI1 NM_005097.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.12

Genes affected

LGI1 (HGNC:6572): (leucine rich glioma inactivated 1) This gene encodes a member of the secreted leucine-rich repeat (LRR) superfamily and shares homology with members of the SLIT protein family. The encoded protein may regulate the activity of voltage-gated potassium channels and may be involved in neuronal growth regulation and cell survival. This gene is rearranged as a result of translocations in glioblastoma cell lines, and it is frequently down-regulated or rearranged in malignant gliomas. Mutations in this gene result in autosomal dominant lateral temporal epilepsy. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Apr 2015]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.20973918).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LGI1	NM_005097.4	c.64T>A	p.Phe22Ile	missense_variant	Exon 1 of 8	ENST00000371418.9	NP_005088.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LGI1	ENST00000371418.9	c.64T>A	p.Phe22Ile	missense_variant	Exon 1 of 8	1	NM_005097.4	ENSP00000360472.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Autosomal dominant epilepsy with auditory features Uncertain:1

Aug 09, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. ClinVar contains an entry for this variant (Variation ID: 1355868). This variant has not been reported in the literature in individuals affected with LGI1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces phenylalanine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 22 of the LGI1 protein (p.Phe22Ile). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.058
BayesDel_addAF	Benign	-0.024	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	19
DANN	Benign	0.92
DEOGEN2	Benign	0.23	T;.;.;.;.;T;T;.
Eigen	Benign	-0.12
Eigen_PC	Benign	0.032
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Uncertain	0.88	D;T;.;.;D;D;D;D
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.21	T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.42	T
MutationAssessor	Benign	1.4	L;.;.;.;L;.;.;L
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-0.21	N;.;.;.;.;.;.;N
REVEL	Benign	0.20
Sift	Benign	0.28	T;.;.;.;.;.;.;T
Sift4G	Benign	0.34	T;T;T;T;T;.;T;T
Polyphen		0.022	B;.;.;.;B;.;.;B
Vest4		0.41
MutPred		0.43		Gain of MoRF binding (P = 0.0964);Gain of MoRF binding (P = 0.0964);Gain of MoRF binding (P = 0.0964);Gain of MoRF binding (P = 0.0964);Gain of MoRF binding (P = 0.0964);Gain of MoRF binding (P = 0.0964);Gain of MoRF binding (P = 0.0964);Gain of MoRF binding (P = 0.0964);
MVP		0.63
MPC		0.99
ClinPred		0.60	D
GERP RS		4.7
Varity_R		0.077
gMVP		0.43

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: chr10-95517965;