rs1365570193

Variant names:

• chr11-95821883-C-A
• rs1365570193
• NM_014679.5:c.712C>A

Your query was ambiguous. Multiple possible variants found:

• chr11-95821883-C-A
• chr11-95821883-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_014679.5(CEP57):​c.712C>A​(p.Leu238Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000686 in 1,458,054 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. L238L) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: CEP57 NM_014679.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.541
• 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.21599242).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CEP57	NM_014679.5	c.712C>A	p.Leu238Ile	missense_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.712C>A	p.Leu238Ile	missense_variant	Exon 7 of 11	1	NM_014679.5	ENSP00000317902.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.86e-7 AC: 1 AN: 1458054 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 725522

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33380

American (AMR) AF: 0.00 AC: 0 AN: 44694

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26092

East Asian (EAS) AF: 0.00 AC: 0 AN: 39600

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86112

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53298

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4708

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1109974

Other (OTH) AF: 0.00 AC: 0 AN: 60196

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.087
BayesDel_addAF	Benign	-0.087	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	20
DANN	Benign	0.97
DEOGEN2	Benign	0.036	T;.;T;.;.
Eigen	Benign	-0.092
Eigen_PC	Benign	-0.028
FATHMM_MKL	Benign	0.71	D
LIST_S2	Benign	0.83	T;T;T;D;T
M_CAP	Benign	0.028	D
MetaRNN	Benign	0.22	T;T;T;T;T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	2.0	.;M;M;M;.
PhyloP100		0.54
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-1.2	N;N;N;N;N
REVEL	Benign	0.10
Sift	Benign	0.13	T;T;T;D;T
Sift4G	Benign	0.089	T;T;T;T;T
Polyphen		0.27, 0.039, 0.020	.;B;B;B;.
Vest4		0.28
MutPred		0.71		.;Gain of catalytic residue at L243 (P = 0.0349);Gain of catalytic residue at L243 (P = 0.0349);Gain of catalytic residue at L243 (P = 0.0349);.;
MVP		0.46
MPC		0.081
ClinPred		0.38	T
GERP RS		2.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.094
gMVP		0.16
Mutation Taster		=86/14	polymorphism

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

Other links and lift over

dbSNP: rs1365570193; hg19: chr11-95555047;