rs267608328

Variant names:

• chrX-154030398-C-G
• rs267608328
• NM_001110792.2:c.1466G>C

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

This summary comes from the ClinGen Evidence Repository: The p.Ser477Thr (NM_004992.3) variant is observed in at least 2 unaffected individuals (PMID:12655490) (BS2). The p.Ser477Thr variant is observed in the MECP2 gene where a second pathogenic variant in the same gene is present in the patient (PMID 12655490); however, it is unknown if the variants are in cis or trans (BP5 - not met). The highest population minor allele frequency of the p.Ser477Thr variant in MECP2 (NM_004992.3) in gnomAD v4.1 is 0.000008933 in European (non-Finnish) population (not sufficient to meet BA1, BS1, or PM2 criteria). In the absence of conflicting evidence, this is sufficient evidence to classify as likely benign based on the specifications defined by the ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel. In summary, the p.Ser477Thr variant in MECP2 (NM_004992.3) is classified as likely benign for Rett syndrome based on the ACMG/AMP criteria (BS2). LINK:https://erepo.genome.network/evrepo/ui/classification/CA170245/MONDO:0010726/036

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0000073 (0 hom. 3 hem.)
• Consequence: MECP2 NM_001110792.2 missense
• Clinical Significance: Likely benign reviewed by expert panel U:1 B:3
• Conservation: PhyloP100: 4.99
• Publications: 0 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 -4 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MECP2	NM_001110792.2	c.1466G>C	p.Ser489Thr	missense_variant	Exon 3 of 3	ENST00000453960.7	NP_001104262.1
MECP2	NM_004992.4	c.1430G>C	p.Ser477Thr	missense_variant	Exon 4 of 4	ENST00000303391.11	NP_004983.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MECP2	ENST00000453960.7	c.1466G>C	p.Ser489Thr	missense_variant	Exon 3 of 3	1	NM_001110792.2	ENSP00000395535.2
MECP2	ENST00000303391.11	c.1430G>C	p.Ser477Thr	missense_variant	Exon 4 of 4	1	NM_004992.4	ENSP00000301948.6

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 0.00000728 AC: 8 AN: 1098234 Hom.: 0 Cov.: 32 AF XY: 0.00000825 AC XY: 3 AN XY: 363588

African (AFR) AF: 0.00 AC: 0 AN: 26402

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: 40523

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

European-Non Finnish (NFE) AF: 0.00000950 AC: 8 AN: 842128

Other (OTH) AF: 0.00 AC: 0 AN: 46096

GnomAD4 genome Cov.: 23

ClinVar

Significance: Likely benign

Submissions summary: Uncertain:1 Benign:3

Revision: reviewed by expert panel

Submissions by phenotype

Rett syndrome Uncertain:1 Benign:1

Mar 14, 2024

Centre for Population Genomics, CPG

Significance: Uncertain significance

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 a variant of uncertain significance. At least the following criteria are met: The variant is observed in at least 2 individuals with no features of Rett Syndrome (BS2).PMID: 12655490 This variant is absent from gnomAD (PM2_Supporting). -

Aug 30, 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.Ser477Thr (NM_004992.3) variant is observed in at least 2 unaffected individuals (PMID: 12655490) (BS2). The p.Ser477Thr variant is observed in the MECP2 gene where a second pathogenic variant in the same gene is present in the patient (PMID 12655490); however, it is unknown if the variants are in cis or trans (BP5 - not met). The highest population minor allele frequency of the p.Ser477Thr variant in MECP2 (NM_004992.3) in gnomAD v4.1 is 0.000008933 in European (non-Finnish) population (not sufficient to meet BA1, BS1, or PM2 criteria). In the absence of conflicting evidence, this is sufficient evidence to classify as likely benign based on the specifications defined by the ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel. In summary, the p.Ser477Thr variant in MECP2 (NM_004992.3) is classified as likely benign for Rett syndrome based on the ACMG/AMP criteria (BS2). -

Severe neonatal-onset encephalopathy with microcephaly Benign:1

Apr 03, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

Nov 01, 2007

RettBASE

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: curation

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.068
BayesDel_addAF	Uncertain	0.062	T
BayesDel_noAF	Benign	-0.15
CADD	Benign	21
DANN	Benign	0.79
DEOGEN2	Benign	0.31	T;.
FATHMM_MKL	Benign	0.38	N
LIST_S2	Benign	0.76	T;T
M_CAP	Uncertain	0.15	D
MetaRNN	Benign	0.088	T;T
MetaSVM	Benign	-0.40	T
MutationAssessor	Benign	-0.11	N;.
PhyloP100		5.0
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	-0.76	N;N
REVEL	Uncertain	0.33
Sift	Benign	0.34	T;T
Sift4G	Benign	0.35	T;T
Polyphen		0.0090	B;B
Vest4		0.067
MutPred		0.22		Gain of glycosylation at S477 (P = 0.2535);.;
MVP		0.94
ClinPred		0.57	D
GERP RS		3.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.31
gMVP		0.27
Mutation Taster		=83/17	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: rs267608328; hg19: chrX-153295849;