X-154031012-C-T

Variant names:

• chrX-154031012-C-T
• rs587783746
• NM_001110792.2:c.852G>A

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 0P and 3B. BP4 BP7 BS2_Supporting

This summary comes from the ClinGen Evidence Repository: The p.Pro272= variant in MECP2 (NM_004992.3) is present in 3 XX and 2 XY individual(s) in gnomAD v2 (0.002%) (not sufficient to meet BS1 criteria). The silent p.Pro272= variant is not predicted to affect splicing using multiple computational tools and does not affect a highly conserved nucleotide (BP4, BP7). The p.Pro272= variant is observed in at least 1 unaffected individual (internal database - Invitae) (BS2_supporting). In summary, the p.Pro272= variant in MECP2 is classified as likely benign based on the ACMG/AMP criteria (BP4, BP7, BS2_supporting). LINK:https://erepo.genome.network/evrepo/ui/classification/CA172580/MONDO:0010726/036

• Frequency:
  • Genomes: 𝑓 0.000027 (0 hom., 2 hem., cov: 23)
  • Exomes 𝑓: 0.000025 (0 hom. 7 hem.)
• Consequence: MECP2 NM_001110792.2 synonymous
• Clinical Significance: Likely benign reviewed by expert panel U:1 B:2
• Conservation: PhyloP100: -6.54
• Publications: 1 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: Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics, ClinGen, 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

Our verdict: Likely_benign. The variant received -3 ACMG points.

• BP4: For more information check the summary or visit ClinGen Evidence Repository.
• BP7: 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MECP2	NM_001110792.2	MANE Select	c.852G>A	p.Pro284Pro	synonymous	Exon 3 of 3	NP_001104262.1
	MECP2	NM_004992.4	MANE Plus Clinical	c.816G>A	p.Pro272Pro	synonymous	Exon 4 of 4	NP_004983.1
	MECP2	NM_001316337.2		c.537G>A	p.Pro179Pro	synonymous	Exon 5 of 5	NP_001303266.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MECP2	ENST00000453960.7	TSL:1 MANE Select	c.852G>A	p.Pro284Pro	synonymous	Exon 3 of 3	ENSP00000395535.2
	MECP2	ENST00000303391.11	TSL:1 MANE Plus Clinical	c.816G>A	p.Pro272Pro	synonymous	Exon 4 of 4	ENSP00000301948.6
	MECP2	ENST00000630151.3	TSL:5	c.816G>A	p.Pro272Pro	synonymous	Exon 4 of 4	ENSP00000486089.2

Frequencies

GnomAD3 genomes AF: 0.0000267 AC: 3 AN: 112465 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.0000647

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000188

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000274 AC: 5 AN: 182175 AF XY: 0.0000297

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: 0.0000616

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000246 AC: 27 AN: 1098205 Hom.: 0 Cov.: 35 AF XY: 0.0000193 AC XY: 7 AN XY: 363569

African (AFR) AF: 0.0000379 AC: 1 AN: 26401

American (AMR) AF: 0.00 AC: 0 AN: 35206

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19383

East Asian (EAS) AF: 0.00 AC: 0 AN: 30206

South Asian (SAS) AF: 0.00 AC: 0 AN: 54148

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40487

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4136

European-Non Finnish (NFE) AF: 0.0000309 AC: 26 AN: 842144

Other (OTH) AF: 0.00 AC: 0 AN: 46094

GnomAD4 genome AF: 0.0000267 AC: 3 AN: 112465 Hom.: 0 Cov.: 23 AF XY: 0.0000578 AC XY: 2 AN XY: 34603

African (AFR) AF: 0.0000647 AC: 2 AN: 30934

American (AMR) AF: 0.00 AC: 0 AN: 10746

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2651

East Asian (EAS) AF: 0.00 AC: 0 AN: 3569

South Asian (SAS) AF: 0.00 AC: 0 AN: 2757

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6179

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 238

European-Non Finnish (NFE) AF: 0.0000188 AC: 1 AN: 53192

Other (OTH) AF: 0.00 AC: 0 AN: 1516

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ClinVar

Significance: Likely benign

Submissions summary: Uncertain:1 Benign:2

Revision: reviewed by expert panel

Submissions by phenotype

not specified Uncertain:1

Oct 01, 2014

Genetic Services Laboratory, University of Chicago

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Severe neonatal-onset encephalopathy with microcephaly Benign:1

Nov 27, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Rett syndrome Benign:1

Feb 23, 2024

ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel

Significance: Likely benign

Review Status: reviewed by expert panel

Collection Method: curation

The p.Pro272= variant in MECP2 (NM_004992.3) is present in 3 XX and 2 XY individual(s) in gnomAD v2 (0.002%) (not sufficient to meet BS1 criteria). The silent p.Pro272= variant is not predicted to affect splicing using multiple computational tools and does not affect a highly conserved nucleotide (BP4, BP7). The p.Pro272= variant is observed in at least 1 unaffected individual (internal database - Invitae) (BS2_supporting). In summary, the p.Pro272= variant in MECP2 is classified as likely benign based on the ACMG/AMP criteria (BP4, BP7, BS2_supporting).

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
CADD	Benign	0.0080
DANN	Benign	0.76
PhyloP100		-6.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Mutation Taster		=100/0	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: rs587783746; hg19: chrX-153296463; COSMIC: COSV100318165; COSMIC: COSV100318165;