rs36021462

Variant names:

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 4P and 13B. PM1PM5BP4_StrongBP6BS1BS2

The NM_001278116.2(L1CAM):c.2302G>A(p.Val768Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00317 in 1,209,763 control chromosomes in the GnomAD database, including 7 homozygotes. There are 1,359 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V768F) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.0019 ( 0 hom., 63 hem., cov: 22)

Exomes 𝑓: 0.0033 ( 7 hom. 1296 hem. )

Consequence

L1CAM
NM_001278116.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:12

Conservation

PhyloP100: 0.348

Variant links:

Genes affected

L1CAM (HGNC:6470): (L1 cell adhesion molecule) The protein encoded by this gene is an axonal glycoprotein belonging to the immunoglobulin supergene family. The ectodomain, consisting of several immunoglobulin-like domains and fibronectin-like repeats (type III), is linked via a single transmembrane sequence to a conserved cytoplasmic domain. This cell adhesion molecule plays an important role in nervous system development, including neuronal migration and differentiation. Mutations in the gene cause X-linked neurological syndromes known as CRASH (corpus callosum hypoplasia, retardation, aphasia, spastic paraplegia and hydrocephalus). Alternative splicing of this gene results in multiple transcript variants, some of which include an alternate exon that is considered to be specific to neurons. [provided by RefSeq, May 2013]

L1CAM links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

PM1

In a domain Fibronectin type-III 2 (size 93) in uniprot entity L1CAM_HUMAN there are 5 pathogenic changes around while only 1 benign (83%) in NM_001278116.2

PM5

Other missense variant is known to change same aminoacid residue: Variant chrnull-null-null-null is described in UniProt as null.

BP4

Computational evidence support a benign effect (MetaRNN=0.004782349).

BP6

Variant X-153866778-C-T is Benign according to our data. Variant chrX-153866778-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 92924.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Benign=6, Likely_benign=3}. Variant chrX-153866778-C-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00186 (208/111901) while in subpopulation SAS AF= 0.00602 (16/2659). AF 95% confidence interval is 0.00377. There are 0 homozygotes in gnomad4. There are 63 alleles in male gnomad4 subpopulation. Median coverage is 22. This position pass quality control queck.

BS2

High Hemizygotes in GnomAd4 at 63 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
L1CAM	NM_001278116.2 link	c.2302G>A	p.Val768Ile	missense_variant	Exon 19 of 29	ENST00000370060.7	NP_001265045.1	P32004-1
L1CAM	NM_000425.5 link	c.2302G>A	p.Val768Ile	missense_variant	Exon 18 of 28		NP_000416.1	P32004-1
L1CAM	NM_024003.3 link	c.2302G>A	p.Val768Ile	missense_variant	Exon 18 of 27		NP_076493.1	P32004-2
L1CAM	NM_001143963.2 link	c.2287G>A	p.Val763Ile	missense_variant	Exon 17 of 26		NP_001137435.1	P32004-3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
L1CAM	ENST00000370060.7 link	c.2302G>A	p.Val768Ile	missense_variant	Exon 19 of 29	5	NM_001278116.2	ENSP00000359077.1		P32004-1

Frequencies

GnomAD3 genomes

AF:

0.00187

AC:

209

AN:

111851

Hom.:

Cov.:

AF XY:

0.00188

AC XY:

AN XY:

34007

show subpopulations

Gnomad AFR

AF:

0.000553

Gnomad AMI

AF:

0.0117

Gnomad AMR

AF:

0.000377

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00600

Gnomad FIN

AF:

0.000327

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00297

Gnomad OTH

AF:

0.00266

GnomAD3 exomes

AF:

0.00214

AC:

392

AN:

183219

Hom.:

AF XY:

0.00276

AC XY:

187

AN XY:

67707

show subpopulations

Gnomad AFR exome

AF:

0.000304

Gnomad AMR exome

AF:

0.000584

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00634

Gnomad FIN exome

AF:

0.000375

Gnomad NFE exome

AF:

0.00291

Gnomad OTH exome

AF:

0.00155

GnomAD4 exome

AF:

0.00331

AC:

3629

AN:

1097862

Hom.:

Cov.:

AF XY:

0.00357

AC XY:

1296

AN XY:

363232

show subpopulations

Gnomad4 AFR exome

AF:

0.000265

Gnomad4 AMR exome

AF:

0.000540

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00589

Gnomad4 FIN exome

AF:

0.000766

Gnomad4 NFE exome

AF:

0.00371

Gnomad4 OTH exome

AF:

0.00254

GnomAD4 genome

AF:

0.00186

AC:

208

AN:

111901

Hom.:

Cov.:

AF XY:

0.00185

AC XY:

AN XY:

34067

show subpopulations

Gnomad4 AFR

AF:

0.000552

Gnomad4 AMR

AF:

0.000377

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00602

Gnomad4 FIN

AF:

0.000327

Gnomad4 NFE

AF:

0.00298

Gnomad4 OTH

AF:

0.00197

Alfa

AF:

0.00281

Hom.:

106

Bravo

AF:

0.00174

TwinsUK

AF:

0.00297

AC:

ALSPAC

AF:

0.00415

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00253

AC:

ExAC

AF:

0.00234

AC:

284

EpiCase

AF:

0.00305

EpiControl

AF:

0.00261

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:12

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:5

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	This variant is associated with the following publications: (PMID: 30487145, 22222883, 9268105) -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 08, 2014	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Sep 14, 2016	- -

not specified

Benign:4

Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Nov 19, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Nov 24, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 23, 2022	Variant summary: L1CAM c.2302G>A (p.Val768Ile) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0021 in 204982 control chromosomes, predominantly at a frequency of 0.0063 within the South Asian subpopulation in the gnomAD database. This frequency is not significantly higher than expected for a pathogenic variant in L1CAM causing L1 Syndrome (0.0021 vs 0.0065), allowing no conclusion about variant significance. Although reported in the literature, to our knowledge, no occurrence/penetrant association of c.2302G>A in individuals affected with L1 Syndrome and no supporting experimental evidence demonstrating its impact on protein function have been reported. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign. -

Spastic paraplegia

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 23, 2025

- -

Inborn genetic diseases

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 09, 2017

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Hereditary spastic paraplegia

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Jul 18, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Benign

-0.57

BayesDel_noAF

Benign

-0.59

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.37

.;T;.;.

FATHMM_MKL

Benign

0.079

LIST_S2

Uncertain

0.91

D;D;.;D

MetaRNN

Benign

0.0048

T;T;T;T

MetaSVM

Benign

-0.86

MutationAssessor

Benign

1.6

.;L;.;L

PrimateAI

Benign

0.43

PROVEAN

Benign

-0.78

N;N;N;N

REVEL

Benign

0.081

Sift

Uncertain

0.0040

D;D;D;D

Sift4G

Uncertain

0.030

D;D;D;D

Polyphen

0.27, 0.64

.;B;.;P

Vest4

0.088

MVP

0.48

MPC

0.74

ClinPred

0.032

GERP RS

4.4

Varity_R

0.30

gMVP

0.77

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over