11-95821872-T-G

Variant names:

• chr11-95821872-T-G
• rs750192070
• NM_014679.5:c.701T>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PP3_Moderate

The NM_014679.5(CEP57):​c.701T>G​(p.Leu234Trp) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.0000131 in 1,451,814 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L234F) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000013 (1 hom.)
• Consequence: CEP57 NM_014679.5 missense, splice_region
• Scores: Splicing: ADA: 0.7116
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 4.35
• Publications: 0 publications found

Genes affected

CEP57 (HGNC:30794): (centrosomal protein 57) This gene encodes a cytoplasmic protein called Translokin. This protein localizes to the centrosome and has a function in microtubular stabilization. The N-terminal half of this protein is required for its centrosome localization and for its multimerization, and the C-terminal half is required for nucleating, bundling and anchoring microtubules to the centrosomes. This protein specifically interacts with fibroblast growth factor 2 (FGF2), sorting nexin 6, Ran-binding protein M and the kinesins KIF3A and KIF3B, and thus mediates the nuclear translocation and mitogenic activity of the FGF2. It also interacts with cyclin D1 and controls nucleocytoplasmic distribution of the cyclin D1 in quiescent cells. This protein is crucial for maintaining correct chromosomal number during cell division. Mutations in this gene cause mosaic variegated aneuploidy syndrome, a rare autosomal recessive disorder. Multiple alternatively spliced transcript variants encoding different isoforms have been identified. [provided by RefSeq, Aug 2011]

MTMR2 (HGNC:7450): (myotubularin related protein 2) This gene is a member of the myotubularin family of phosphoinositide lipid phosphatases. The encoded protein possesses phosphatase activity towards phosphatidylinositol-3-phosphate and phosphatidylinositol-3,5-bisphosphate. Mutations in this gene are a cause of Charcot-Marie-Tooth disease type 4B, an autosomal recessive demyelinating neuropathy. Alternatively spliced transcript variants encoding multiple isoforms have been found for this gene. [provided by RefSeq, Aug 2011]

MTMR2 Gene-Disease associations (from GenCC):

• demyelinating hereditary motor and sensory neuropathy

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• Charcot-Marie-Tooth disease type 4B1

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.879

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CEP57	NM_014679.5	c.701T>G	p.Leu234Trp	missense_variant, splice_region_variant	Exon 7 of 11	ENST00000325542.10	NP_055494.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CEP57	ENST00000325542.10	c.701T>G	p.Leu234Trp	missense_variant, splice_region_variant	Exon 7 of 11	1	NM_014679.5	ENSP00000317902.5

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152122 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000320 AC: 8 AN: 250168 AF XY: 0.0000517

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000266

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000131 AC: 19 AN: 1451814 Hom.: 1 Cov.: 28 AF XY: 0.0000207 AC XY: 15 AN XY: 722892

African (AFR) AF: 0.00 AC: 0 AN: 33264

American (AMR) AF: 0.00 AC: 0 AN: 44680

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26050

East Asian (EAS) AF: 0.00 AC: 0 AN: 39558

South Asian (SAS) AF: 0.000105 AC: 9 AN: 86042

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53286

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4540

European-Non Finnish (NFE) AF: 0.00000815 AC: 9 AN: 1104376

Other (OTH) AF: 0.0000167 AC: 1 AN: 60018

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ExAC AF: 0.0000494 AC: 6

EpiCase AF: 0.000164

EpiControl AF: 0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Jun 07, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.701T>G (p.L234W) alteration is located in exon 7 (coding exon 7) of the CEP57 gene. This alteration results from a T to G substitution at nucleotide position 701, causing the leucine (L) at amino acid position 234 to be replaced by a tryptophan (W). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Mosaic variegated aneuploidy syndrome 2 Uncertain:1

Nov 13, 2018

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 disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with CEP57-related disease. This variant is present in population databases (rs750192070, ExAC 0.02%). This sequence change replaces leucine with tryptophan at codon 234 of the CEP57 protein (p.Leu234Trp). The leucine residue is highly conserved and there is a small physicochemical difference between leucine and tryptophan. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.41
BayesDel_addAF	Uncertain	0.10	D
BayesDel_noAF	Pathogenic	0.17
CADD	Pathogenic	30
DANN	Benign	0.97
DEOGEN2	Benign	0.34	T;.;T;.;.
Eigen	Pathogenic	0.75
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.94	D;D;D;D;D
M_CAP	Uncertain	0.12	D
MetaRNN	Pathogenic	0.88	D;D;D;D;D
MetaSVM	Uncertain	-0.21	T
MutationAssessor	Uncertain	2.8	.;M;M;M;.
PhyloP100		4.4
PrimateAI	Uncertain	0.65	T
PROVEAN	Pathogenic	-4.9	D;D;D;D;D
REVEL	Uncertain	0.64
Sift	Uncertain	0.0010	D;D;D;D;D
Sift4G	Uncertain	0.0020	D;D;D;D;D
Polyphen		1.0	.;D;D;D;.
Vest4		0.72
MutPred		0.80		.;Gain of MoRF binding (P = 0.0256);Gain of MoRF binding (P = 0.0256);Gain of MoRF binding (P = 0.0256);.;
MVP		0.66
MPC		0.50
ClinPred		0.77	D
GERP RS		6.1
Varity_R		0.46
gMVP		0.59
Mutation Taster		=90/10	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.71
dbscSNV1_RF	Benign	0.61
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

Other links and lift over

dbSNP: rs750192070; hg19: chr11-95555036;