rs61753006

Variant names:

• chrX-154030665-G-A
• rs61753006
• NM_001110792.2:c.1199C>T

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BS1 BS2

This summary comes from the ClinGen Evidence Repository: The allele frequency of the p.Pro388Leu (NM_004992.3) variant in MECP2 is 0.014% in Latino sub population in gnomAD, which is high enough to be classified as likely benign based on thresholds defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like conditions (BS1). Thep.Pro388Leu variant is observed in at least 2 unaffected individuals (GeneDx internal database) (BS2). In summary, the p.Pro388Leu variant in MECP2 is classified as benign based on the ACMG/AMP criteria (BS1, BS2). LINK:https://erepo.genome.network/evrepo/ui/classification/CA270246/MONDO:0010726/016

• Frequency:
  • Genomes: 𝑓 0.000018 (0 hom., 0 hem., cov: 21)
  • Exomes 𝑓: 0.000026 (0 hom. 8 hem.)
• Consequence: MECP2 NM_001110792.2 missense
• Clinical Significance: Benign reviewed by expert panel U:1 B:5
• Conservation: PhyloP100: 3.20
• Publications: 2 publications found

Genes affected

MECP2 (HGNC:6990): (methyl-CpG binding protein 2) DNA methylation is the major modification of eukaryotic genomes and plays an essential role in mammalian development. Human proteins MECP2, MBD1, MBD2, MBD3, and MBD4 comprise a family of nuclear proteins related by the presence in each of a methyl-CpG binding domain (MBD). Each of these proteins, with the exception of MBD3, is capable of binding specifically to methylated DNA. MECP2, MBD1 and MBD2 can also repress transcription from methylated gene promoters. In contrast to other MBD family members, MECP2 is X-linked and subject to X inactivation. MECP2 is dispensible in stem cells, but is essential for embryonic development. MECP2 gene mutations are the cause of most cases of Rett syndrome, a progressive neurologic developmental disorder and one of the most common causes of cognitive disability in females. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Oct 2015]

MECP2 Gene-Disease associations (from GenCC):

• chromosome Xq28 duplication syndrome

  Inheritance: XL Classification: DEFINITIVE Submitted by: G2P
• Rett syndrome

  Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, Ambry Genetics, Orphanet, G2P
• severe neonatal-onset encephalopathy with microcephaly

  Inheritance: XL Classification: DEFINITIVE, SUPPORTIVE Submitted by: G2P, Orphanet
• syndromic X-linked intellectual disability Lubs type

  Inheritance: XL Classification: DEFINITIVE Submitted by: G2P
• atypical Rett syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• non-syndromic X-linked intellectual disability

  Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet
• X-linked intellectual disability-psychosis-macroorchidism syndrome

  Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet
• systemic lupus erythematosus

  Inheritance: Unknown Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Specifications for MECP2 are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Benign. The variant received -8 ACMG points.

• BS1: For more information check the summary or visit ClinGen Evidence Repository.
• BS2: For more information check the summary or visit ClinGen Evidence Repository.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001110792.2. 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
	MECP2	NM_001110792.2	MANE Select	c.1199C>T	p.Pro400Leu	missense	Exon 3 of 3	NP_001104262.1	A0A140VKC4
	MECP2	NM_004992.4	MANE Plus Clinical	c.1163C>T	p.Pro388Leu	missense	Exon 4 of 4	NP_004983.1	D3YJ43
	MECP2	NM_001316337.2		c.884C>T	p.Pro295Leu	missense	Exon 5 of 5	NP_001303266.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MECP2	ENST00000453960.7	TSL:1 MANE Select	c.1199C>T	p.Pro400Leu	missense	Exon 3 of 3	ENSP00000395535.2	P51608-2
	MECP2	ENST00000303391.11	TSL:1 MANE Plus Clinical	c.1163C>T	p.Pro388Leu	missense	Exon 4 of 4	ENSP00000301948.6	P51608-1
	MECP2	ENST00000630151.3	TSL:5	c.1163C>T	p.Pro388Leu	missense	Exon 4 of 4	ENSP00000486089.2	P51608-1

Frequencies

GnomAD3 genomes AF: 0.0000184 AC: 2 AN: 108873 Hom.: 0 Cov.: 21

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000971

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000192

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000173 AC: 3 AN: 173056 AF XY: 0.0000158

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000110

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000257 AC: 28 AN: 1087952 Hom.: 0 Cov.: 35 AF XY: 0.0000225 AC XY: 8 AN XY: 356208

African (AFR) AF: 0.0000381 AC: 1 AN: 26249

American (AMR) AF: 0.0000854 AC: 3 AN: 35144

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19328

East Asian (EAS) AF: 0.000298 AC: 9 AN: 30152

South Asian (SAS) AF: 0.0000185 AC: 1 AN: 53923

European-Finnish (FIN) AF: 0.0000273 AC: 1 AN: 36685

Middle Eastern (MID) AF: 0.000274 AC: 1 AN: 3645

European-Non Finnish (NFE) AF: 0.0000143 AC: 12 AN: 837020

Other (OTH) AF: 0.00 AC: 0 AN: 45806

GnomAD4 genome AF: 0.0000184 AC: 2 AN: 108873 Hom.: 0 Cov.: 21 AF XY: 0.00 AC XY: 0 AN XY: 31159

African (AFR) AF: 0.00 AC: 0 AN: 29831

American (AMR) AF: 0.0000971 AC: 1 AN: 10296

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2606

East Asian (EAS) AF: 0.00 AC: 0 AN: 3451

South Asian (SAS) AF: 0.00 AC: 0 AN: 2471

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5803

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 237

European-Non Finnish (NFE) AF: 0.0000192 AC: 1 AN: 52037

Other (OTH) AF: 0.00 AC: 0 AN: 1464

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000264

ClinVar

ClinVar submissions

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	1	2	Rett syndrome (3)
-	-	1	MECP2-related disorder (1)
-	-	1	not provided (1)
-	-	1	Severe neonatal-onset encephalopathy with microcephaly (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_addAF	Uncertain	0.081	D
BayesDel_noAF	Uncertain	0.090
CADD	Benign	17
DANN	Benign	0.21
DEOGEN2	Benign	0.27	T
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Benign	0.86	D
M_CAP	Pathogenic	0.53	D
MetaRNN	Uncertain	0.68	D
MetaSVM	Benign	-0.45	T
MutationAssessor	Benign	0.0	N
PhyloP100		3.2
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-0.78	N
REVEL	Uncertain	0.48
Sift	Benign	0.36	T
Sift4G	Benign	0.076	T
Polyphen		0.0	B
Vest4		0.48
MutPred		0.78		Loss of glycosylation at P388 (P = 0.0016)
MVP		0.99
ClinPred		0.035	T
GERP RS		4.8
Varity_R		0.11
gMVP		0.41
Mutation Taster		=87/13	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: rs61753006; hg19: chrX-153296116;