NM_001278116.2:c.1268-10C>G

Variant names:

• chrX-153868962-G-C
• rs112841948
• NM_001278116.2:c.1268-10C>G

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_001278116.2(L1CAM):​c.1268-10C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000594 in 1,178,941 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 2 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.000018 (0 hom., 2 hem., cov: 24)
  • Exomes 𝑓: 0.0000047 (0 hom. 0 hem.)
• Consequence: L1CAM NM_001278116.2 intron
• Scores: Splicing: ADA: 0.00006826
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.344
• Publications: 3 publications found

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 Gene-Disease associations (from GenCC):

• L1 syndrome

  Inheritance: XL Classification: DEFINITIVE Submitted by: ClinGen
• X-linked hydrocephalus with stenosis of the aqueduct of Sylvius

  Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet, G2P
• MASA syndrome

  Inheritance: XL Classification: STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet
• X-linked complicated corpus callosum dysgenesis

  Inheritance: XL Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• X-linked complicated spastic paraplegia type 1

  Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BP6: Variant X-153868962-G-C is Benign according to our data. Variant chrX-153868962-G-C is described in ClinVar as Likely_benign. ClinVar VariationId is 2109161.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Hemizygotes in GnomAd4 at 2 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
L1CAM	NM_001278116.2	c.1268-10C>G		intron_variant	Intron 11 of 28	ENST00000370060.7	NP_001265045.1
L1CAM	NM_000425.5	c.1268-10C>G		intron_variant	Intron 10 of 27		NP_000416.1
L1CAM	NM_024003.3	c.1268-10C>G		intron_variant	Intron 10 of 26		NP_076493.1
L1CAM	NM_001143963.2	c.1253-10C>G		intron_variant	Intron 9 of 25		NP_001137435.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
L1CAM	ENST00000370060.7	c.1268-10C>G		intron_variant	Intron 11 of 28	5	NM_001278116.2	ENSP00000359077.1

Frequencies

GnomAD3 genomes AF: 0.0000178 AC: 2 AN: 112260 Hom.: 0 Cov.: 24

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000187

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000547 AC: 1 AN: 182676 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000365

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000469 AC: 5 AN: 1066681 Hom.: 0 Cov.: 28 AF XY: 0.00 AC XY: 0 AN XY: 334825

African (AFR) AF: 0.00 AC: 0 AN: 25875

American (AMR) AF: 0.000142 AC: 5 AN: 35173

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19182

East Asian (EAS) AF: 0.00 AC: 0 AN: 30107

South Asian (SAS) AF: 0.00 AC: 0 AN: 53437

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40379

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4042

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 813447

Other (OTH) AF: 0.00 AC: 0 AN: 45039

GnomAD4 genome AF: 0.0000178 AC: 2 AN: 112260 Hom.: 0 Cov.: 24 AF XY: 0.0000581 AC XY: 2 AN XY: 34412

African (AFR) AF: 0.00 AC: 0 AN: 30751

American (AMR) AF: 0.000187 AC: 2 AN: 10678

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2655

East Asian (EAS) AF: 0.00 AC: 0 AN: 3600

South Asian (SAS) AF: 0.00 AC: 0 AN: 2721

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6213

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 239

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 53206

Other (OTH) AF: 0.00 AC: 0 AN: 1506

Alfa AF: 0.00 Hom.: 53

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Spastic paraplegia Benign:1

Nov 19, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	13
DANN	Benign	0.43
PhyloP100		0.34
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000068
dbscSNV1_RF	Benign	0.028
SpliceAI score (max)		0.17		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs112841948; hg19: chrX-153134417;