rs36021462

Variant names:

• chrX-153866778-C-G
• NM_001278116.2:c.2302G>C

Your query was ambiguous. Multiple possible variants found:

• chrX-153866778-C-G
• chrX-153866778-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 6P and 2B. PM1 PM2 PM5 BP4_Moderate

The NM_001278116.2(L1CAM):​c.2302G>C​(p.Val768Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000911 in 1,097,862 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. 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: not found (cov: 22)
  • Exomes 𝑓: 9.1e-7 (0 hom. 1 hem.)
• Consequence: L1CAM NM_001278116.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.348

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 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
• PM2: Very rare variant in population databases, with high coverage
• 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=0.21439624).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
L1CAM	NM_001278116.2	c.2302G>C	p.Val768Leu	missense_variant	Exon 19 of 29	ENST00000370060.7	NP_001265045.1
L1CAM	NM_000425.5	c.2302G>C	p.Val768Leu	missense_variant	Exon 18 of 28		NP_000416.1
L1CAM	NM_024003.3	c.2302G>C	p.Val768Leu	missense_variant	Exon 18 of 27		NP_076493.1
L1CAM	NM_001143963.2	c.2287G>C	p.Val763Leu	missense_variant	Exon 17 of 26		NP_001137435.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
L1CAM	ENST00000370060.7	c.2302G>C	p.Val768Leu	missense_variant	Exon 19 of 29	5	NM_001278116.2	ENSP00000359077.1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome AF: 9.11e-7 AC: 1 AN: 1097862 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 1 AN XY: 363232

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000185

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 22

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.59
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.67
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.47	.;T;.;.
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.84	T;T;.;T
M_CAP	Uncertain	0.087	D
MetaRNN	Benign	0.21	T;T;T;T
MetaSVM	Benign	-0.68	T
MutationAssessor	Benign	1.6	.;L;.;L
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-2.1	N;N;N;N
REVEL	Benign	0.12
Sift	Uncertain	0.012	D;D;D;D
Sift4G	Uncertain	0.021	D;D;D;D
Polyphen		0.062, 0.24	.;B;.;B
Vest4		0.078
MutPred		0.67		.;Loss of glycosylation at S769 (P = 0.1162);.;Loss of glycosylation at S769 (P = 0.1162);
MVP		0.50
MPC		0.59
ClinPred		0.53	D
GERP RS		4.4
Varity_R		0.46
gMVP		0.90

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: chrX-153132233;