NM_001110792.2:c.553C>A

Variant names:

• chrX-154031311-G-T
• rs61748427
• NM_001110792.2:c.553C>A

Variant summary

Our verdict is Uncertain significance. The variant received -1 ACMG points: 0P and 1B. BS2_Supporting

This summary comes from the ClinGen Evidence Repository: The highest population minor allele frequency of the p.Pro173Thr variant in MECP2 (NM_004992.4) in gnomAD v4.1 is 0.000002233 in European (non-Finnish) population (not sufficient to meet BS1 criteria). The p.Pro173Thr variant is observed in at least 1 unaffected individual (internal database - GeneDx) (BS2_Supporting). The p.Pro173Thr variant is not currently published and is not present in additional databases (internal and publicly available), therefore, no additional criteria are applicable at this time. In summary, the p.Pro173Thr variant in MECP2 is classified as a variant of uncertain significance based on the ACMG/AMP criteria (BS2_Supporting). (MECP2 specification v3.0.0, curation approved on 8/30/2024) LINK:https://erepo.genome.network/evrepo/ui/classification/CA415173958/MONDO:0010726/036

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0000027 (0 hom. 1 hem.)
• Consequence: MECP2 NM_001110792.2 missense
• Clinical Significance: Uncertain significance reviewed by expert panel P:1 U:2
• Conservation: PhyloP100: 6.25
• 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: Uncertain_significance. The variant received -1 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.553C>A	p.Pro185Thr	missense_variant	Exon 3 of 3	ENST00000453960.7	NP_001104262.1
MECP2	NM_004992.4	c.517C>A	p.Pro173Thr	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.553C>A	p.Pro185Thr	missense_variant	Exon 3 of 3	1	NM_001110792.2	ENSP00000395535.2
MECP2	ENST00000303391.11	c.517C>A	p.Pro173Thr	missense_variant	Exon 4 of 4	1	NM_004992.4	ENSP00000301948.6

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 0.00000273 AC: 3 AN: 1098243 Hom.: 0 Cov.: 34 AF XY: 0.00000275 AC XY: 1 AN XY: 363597

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: 19385

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: 40534

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

European-Non Finnish (NFE) AF: 0.00000237 AC: 2 AN: 842128

Other (OTH) AF: 0.0000217 AC: 1 AN: 46096

GnomAD4 genome Cov.: 23

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:2

Revision: reviewed by expert panel

Submissions by phenotype

Rett syndrome Pathogenic:1 Uncertain:1

Aug 30, 2024

ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel

Significance: Uncertain significance

Review Status: reviewed by expert panel

Collection Method: curation

The highest population minor allele frequency of the p.Pro173Thr variant in MECP2 (NM_004992.4) in gnomAD v4.1 is 0.000002233 in European (non-Finnish) population (not sufficient to meet BS1 criteria). The p.Pro173Thr variant is observed in at least 1 unaffected individual (internal database - GeneDx) (BS2_Supporting). The p.Pro173Thr variant is not currently published and is not present in additional databases (internal and publicly available), therefore, no additional criteria are applicable at this time. In summary, the p.Pro173Thr variant in MECP2 is classified as a variant of uncertain significance based on the ACMG/AMP criteria (BS2_Supporting). (MECP2 specification v3.0.0, curation approved on 8/30/2024) -

May 28, 2019

Mendelics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Uncertain:1

Aug 16, 2022

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.23
CADD	Uncertain	23
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.45	T;.;T;T
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.88	D;D;D;D
M_CAP	Pathogenic	0.80	D
MetaRNN	Uncertain	0.72	D;D;D;D
MetaSVM	Uncertain	0.57	D
MutationAssessor	Benign	1.9	L;.;.;.
PhyloP100		6.2
PrimateAI	Uncertain	0.73	T
PROVEAN	Benign	-2.0	N;N;.;.
REVEL	Uncertain	0.57
Sift	Uncertain	0.0030	D;D;.;.
Sift4G	Uncertain	0.0090	D;D;.;D
Polyphen		0.041	B;B;.;.
Vest4		0.18
MutPred		0.34		Gain of phosphorylation at P173 (P = 0.0021);.;Gain of phosphorylation at P173 (P = 0.0021);.;
MVP		0.97
ClinPred		0.89	D
GERP RS		5.5
Varity_R		0.54
gMVP		0.83
Mutation Taster		=37/63	disease causing (ClinVar)

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: rs61748427; hg19: chrX-153296762;