rs61903295

Variant names:

• chr11-95821969-A-G
• rs61903295
• NM_014679.5:c.798A>G

Your query was ambiguous. Multiple possible variants found:

• chr11-95821969-A-G
• chr11-95821969-A-T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_014679.5(CEP57):​c.798A>G​(p.Pro266Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0328 in 1,610,584 control chromosomes in the GnomAD database, including 1,024 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. P266P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.029 (87 hom., cov: 32)
  • Exomes 𝑓: 0.033 (937 hom.)
• Consequence: CEP57 NM_014679.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.79
• Publications: 4 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.019).
• BP6: Variant 11-95821969-A-G is Benign according to our data. Variant chr11-95821969-A-G is described in ClinVar as Benign. ClinVar VariationId is 414983.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.79 with no splicing effect.
• BA1: GnomAdExome4 highest subpopulation (MID) allele frequency at 95% confidence interval = 0.0647 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CEP57	NM_014679.5	MANE Select	c.798A>G	p.Pro266Pro	synonymous	Exon 7 of 11	NP_055494.2
	CEP57	NM_001243776.2		c.771A>G	p.Pro257Pro	synonymous	Exon 8 of 12	NP_001230705.1
	CEP57	NM_001243777.2		c.798A>G	p.Pro266Pro	synonymous	Exon 7 of 10	NP_001230706.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CEP57	ENST00000325542.10	TSL:1 MANE Select	c.798A>G	p.Pro266Pro	synonymous	Exon 7 of 11	ENSP00000317902.5
	CEP57	ENST00000325486.9	TSL:1	c.798A>G	p.Pro266Pro	synonymous	Exon 7 of 10	ENSP00000317487.5
	CEP57	ENST00000538658.5	TSL:1	c.798A>G	p.Pro266Pro	synonymous	Exon 7 of 7	ENSP00000445706.1

Frequencies

GnomAD3 genomes AF: 0.0290 AC: 4411 AN: 152118 Hom.: 87 Cov.: 32

Gnomad AFR AF: 0.00937

Gnomad AMI AF: 0.0219

Gnomad AMR AF: 0.0361

Gnomad ASJ AF: 0.0553

Gnomad EAS AF: 0.000961

Gnomad SAS AF: 0.0135

Gnomad FIN AF: 0.0486

Gnomad MID AF: 0.0791

Gnomad NFE AF: 0.0377

Gnomad OTH AF: 0.0415

GnomAD2 exomes AF: 0.0324 AC: 8079 AN: 249316 AF XY: 0.0328

Gnomad AFR exome AF: 0.00728

Gnomad AMR exome AF: 0.0248

Gnomad ASJ exome AF: 0.0646

Gnomad EAS exome AF: 0.0000547

Gnomad FIN exome AF: 0.0493

Gnomad NFE exome AF: 0.0414

Gnomad OTH exome AF: 0.0439

GnomAD4 exome AF: 0.0332 AC: 48485 AN: 1458348 Hom.: 937 Cov.: 30 AF XY: 0.0333 AC XY: 24138 AN XY: 725632

African (AFR) AF: 0.00856 AC: 286 AN: 33408

American (AMR) AF: 0.0256 AC: 1142 AN: 44652

Ashkenazi Jewish (ASJ) AF: 0.0674 AC: 1756 AN: 26068

East Asian (EAS) AF: 0.0000505 AC: 2 AN: 39588

South Asian (SAS) AF: 0.0158 AC: 1359 AN: 86114

European-Finnish (FIN) AF: 0.0519 AC: 2767 AN: 53264

Middle Eastern (MID) AF: 0.0706 AC: 374 AN: 5294

European-Non Finnish (NFE) AF: 0.0348 AC: 38625 AN: 1109714

Other (OTH) AF: 0.0361 AC: 2174 AN: 60246

GnomAD4 genome AF: 0.0290 AC: 4414 AN: 152236 Hom.: 87 Cov.: 32 AF XY: 0.0293 AC XY: 2184 AN XY: 74438

African (AFR) AF: 0.00936 AC: 389 AN: 41544

American (AMR) AF: 0.0360 AC: 551 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0553 AC: 192 AN: 3470

East Asian (EAS) AF: 0.000963 AC: 5 AN: 5190

South Asian (SAS) AF: 0.0135 AC: 65 AN: 4816

European-Finnish (FIN) AF: 0.0486 AC: 516 AN: 10610

Middle Eastern (MID) AF: 0.0918 AC: 27 AN: 294

European-Non Finnish (NFE) AF: 0.0377 AC: 2562 AN: 67984

Other (OTH) AF: 0.0411 AC: 87 AN: 2116

Alfa AF: 0.0359 Hom.: 62

Bravo AF: 0.0272

Asia WGS AF: 0.0100 AC: 35 AN: 3478

EpiCase AF: 0.0417

EpiControl AF: 0.0442

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	CEP57-related disorder (1)
-	-	1	Mosaic variegated aneuploidy syndrome 2 (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.27
CADD	Benign	10
DANN	Benign	0.88
PhyloP100		1.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
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: rs61903295; hg19: chr11-95555133;