rs61750257

Variant names:

• chrX-154030969-C-G
• rs61750257
• NM_001110792.2:c.895G>C

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP5 BS2 BP2

This summary comes from the ClinGen Evidence Repository: The p.Ala287Pro variant in MECP2 (NM_004992.3) is observed in at least 2 unaffected individuals (internal database - GeneDx, internal database - Baylor) (BS2). The p.Ala287Pro variant is observed in the MECP2 gene where a second pathogenic variant in the same gene is present in the patient (internal database - GeneDx) (BP2). The p.Ala287Pro variant is found in a patient with an alternate molecular basis of disease (internal database - Baylor) (BP5). The p.Ala287Pro variant in MECP2 is present in gnomAD v2.1.1 at a frequency of 0.001638% (no criteria met). In summary, the p.Ala287Pro variant in MECP2 is classified as Likely Benign based on the ACMG/AMP criteria (BS2, BP2, BP5). LINK:https://erepo.genome.network/evrepo/ui/classification/CA270538/MONDO:0010726/016

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.000010 (0 hom. 4 hem.)
• Consequence: MECP2 NM_001110792.2 missense
• Clinical Significance: Likely benign reviewed by expert panel U:1 B:4
• Conservation: PhyloP100: 3.39
• 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: 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 -6 ACMG points.

• BP2: For more information check the summary or visit ClinGen Evidence Repository.
• BP5: 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.895G>C	p.Ala299Pro	missense	Exon 3 of 3	NP_001104262.1
	MECP2	NM_004992.4	MANE Plus Clinical	c.859G>C	p.Ala287Pro	missense	Exon 4 of 4	NP_004983.1
	MECP2	NM_001316337.2		c.580G>C	p.Ala194Pro	missense	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.895G>C	p.Ala299Pro	missense	Exon 3 of 3	ENSP00000395535.2
	MECP2	ENST00000303391.11	TSL:1 MANE Plus Clinical	c.859G>C	p.Ala287Pro	missense	Exon 4 of 4	ENSP00000301948.6
	MECP2	ENST00000630151.3	TSL:5	c.859G>C	p.Ala287Pro	missense	Exon 4 of 4	ENSP00000486089.2

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD2 exomes AF: 0.0000164 AC: 3 AN: 183189 AF XY: 0.0000295

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: 0.0000367

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000100 AC: 11 AN: 1098220 Hom.: 0 Cov.: 35 AF XY: 0.0000110 AC XY: 4 AN XY: 363582

African (AFR) AF: 0.00 AC: 0 AN: 26403

American (AMR) AF: 0.00 AC: 0 AN: 35207

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19386

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 54149

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40485

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4137

European-Non Finnish (NFE) AF: 0.0000119 AC: 10 AN: 842150

Other (OTH) AF: 0.0000217 AC: 1 AN: 46097

GnomAD4 genome Cov.: 23

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000149 AC: 1

ExAC AF: 0.0000412 AC: 5

ClinVar

Significance: Likely benign

Submissions summary: Uncertain:1 Benign:4

Revision: reviewed by expert panel

Submissions by phenotype

Rett syndrome Uncertain:1 Benign:2

Apr 10, 2002

RettBASE

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: curation

Mar 26, 2024

Centre for Population Genomics, CPG

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: curation

This variant has been collected from RettBASE and curated to current modified ACMG/AMP criteria. Based on the classification scheme defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like Disorders Specifications to the ACMG/AMP Variant Interpretation Guidelines VCEP 3.0, this variant is classified as likely benign. At least the following criteria are met: The variant is observed in at least 2 individuals with no features of Rett Syndrome (BS2). ClinVar Variation ID: 143716, present in 11 individuals in gnomAD v4 including 4 hemizygous (max AF < 0.008%)

Oct 28, 2021

ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel

Significance: Likely benign

Review Status: reviewed by expert panel

Collection Method: curation

The p.Ala287Pro variant in MECP2 (NM_004992.3) is observed in at least 2 unaffected individuals (internal database - GeneDx, internal database - Baylor) (BS2). The p.Ala287Pro variant is observed in the MECP2 gene where a second pathogenic variant in the same gene is present in the patient (internal database - GeneDx) (BP2). The p.Ala287Pro variant is found in a patient with an alternate molecular basis of disease (internal database - Baylor) (BP5). The p.Ala287Pro variant in MECP2 is present in gnomAD v2.1.1 at a frequency of 0.001638% (no criteria met). In summary, the p.Ala287Pro variant in MECP2 is classified as Likely Benign based on the ACMG/AMP criteria (BS2, BP2, BP5).

not specified Benign:1

Mar 03, 2016

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.

Severe neonatal-onset encephalopathy with microcephaly Benign:1

Dec 30, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.30
BayesDel_addAF	Pathogenic	0.44	D
BayesDel_noAF	Pathogenic	0.51
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.46	T
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.93	D
M_CAP	Pathogenic	0.93	D
MetaRNN	Pathogenic	0.76	D
MetaSVM	Uncertain	0.39	D
MutationAssessor	Benign	2.0	M
PhyloP100		3.4
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-0.21	N
REVEL	Uncertain	0.55
Sift	Uncertain	0.0020	D
Sift4G	Benign	0.28	T
Polyphen		1.0	D
Vest4		0.69
MVP		1.0
ClinPred		0.52	D
GERP RS		4.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.44
gMVP		0.87
Mutation Taster		=49/51	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs61750257; hg19: chrX-153296420;