rs631099

Variant names:

• chr11-95830318-T-C
• rs631099
• NM_014679.5:c.1273-708T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_014679.5(CEP57):​c.1273-708T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.278 in 152,052 control chromosomes in the GnomAD database, including 7,069 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.28 (7069 hom., cov: 32)
• Consequence: CEP57 NM_014679.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.39
• Publications: 3 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.98).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.376 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014679.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CEP57	NM_014679.5	MANE Select	c.1273-708T>C		intron	N/A	NP_055494.2
	CEP57	NM_001243776.2		c.1246-708T>C		intron	N/A	NP_001230705.1	Q86XR8-5
	CEP57	NM_001243777.2		c.1195-708T>C		intron	N/A	NP_001230706.1	Q86XR8-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CEP57	ENST00000325542.10	TSL:1 MANE Select	c.1273-708T>C		intron	N/A	ENSP00000317902.5	Q86XR8-1
	CEP57	ENST00000325486.9	TSL:1	c.1195-708T>C		intron	N/A	ENSP00000317487.5	Q86XR8-2
	CEP57	ENST00000540830.5	TSL:1	n.*1037-708T>C		intron	N/A	ENSP00000440996.1	F5GXS6

Frequencies

GnomAD3 genomes AF: 0.279 AC: 42317 AN: 151934 Hom.: 7064 Cov.: 32

Gnomad AFR AF: 0.116

Gnomad AMI AF: 0.351

Gnomad AMR AF: 0.268

Gnomad ASJ AF: 0.527

Gnomad EAS AF: 0.262

Gnomad SAS AF: 0.157

Gnomad FIN AF: 0.245

Gnomad MID AF: 0.288

Gnomad NFE AF: 0.380

Gnomad OTH AF: 0.327

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.278 AC: 42326 AN: 152052 Hom.: 7069 Cov.: 32 AF XY: 0.270 AC XY: 20048 AN XY: 74336

African (AFR) AF: 0.116 AC: 4822 AN: 41496

American (AMR) AF: 0.267 AC: 4071 AN: 15254

Ashkenazi Jewish (ASJ) AF: 0.527 AC: 1830 AN: 3472

East Asian (EAS) AF: 0.263 AC: 1358 AN: 5166

South Asian (SAS) AF: 0.157 AC: 757 AN: 4824

European-Finnish (FIN) AF: 0.245 AC: 2594 AN: 10572

Middle Eastern (MID) AF: 0.289 AC: 85 AN: 294

European-Non Finnish (NFE) AF: 0.379 AC: 25788 AN: 67958

Other (OTH) AF: 0.333 AC: 702 AN: 2106

Alfa AF: 0.314 Hom.: 1098

Bravo AF: 0.278

Asia WGS AF: 0.223 AC: 773 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.98
CADD	Benign	1.2
DANN	Benign	0.55
PhyloP100		-1.4
Mutation Taster		=100/0	polymorphism (auto)

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: rs631099; hg19: chr11-95563482;