X-154030747-G-C

Variant names:

• chrX-154030747-G-C
• rs61752373
• NM_001110792.2:c.1117C>G
• MECP2 p.Pro373Ala

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP5 BS2

This summary comes from the ClinGen Evidence Repository: The allele frequency of p.Pro361Ala variant in MECP2 (NM_004992) gene in the European (non-Finnish) subpopulation in gnomAD is 0.005% which does not satisfy any of the population frequency criteria for this disorder. The p.Pro361Ala variant is observed as 3 hemizygotes in 6 occurrences in gnomAD (BS2). The p.Pro361Ala variant is found in a patient with an alternate molecular basis of disease (Invitae internal database) (BP5). The p.Pro361Ala variant does not occur in either well-characterized functional domain of the MECP2. The in silico evidence is inconclusive for the variant. In summary, the p.Pro361Ala variant in MECP2 is classified as Likely Benign based on ACMG/AMP criteria (BS2, BP5). LINK:https://erepo.genome.network/evrepo/ui/classification/CA170169/MONDO:0010726/016

• Frequency:
  • Genomes: 𝑓 0.000018 (0 hom., 1 hem., cov: 22)
  • Exomes 𝑓: 0.000091 (0 hom. 36 hem.)
• Consequence: MECP2 NM_001110792.2 missense
• Clinical Significance: Benign reviewed by expert panel U:2 B:4
• Conservation: PhyloP100: 1.48
• 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), Ambry Genetics, Orphanet, G2P, ClinGen
• 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: Likely_benign. The variant received -5 ACMG points.

• 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MECP2	NM_001110792.2	MANE Select	c.1117C>G	p.Pro373Ala	missense	Exon 3 of 3	NP_001104262.1	A0A140VKC4
	MECP2	NM_004992.4	MANE Plus Clinical	c.1081C>G	p.Pro361Ala	missense	Exon 4 of 4	NP_004983.1	D3YJ43
	MECP2	NM_001316337.2		c.802C>G	p.Pro268Ala	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.1117C>G	p.Pro373Ala	missense	Exon 3 of 3	ENSP00000395535.2	P51608-2
	MECP2	ENST00000303391.11	TSL:1 MANE Plus Clinical	c.1081C>G	p.Pro361Ala	missense	Exon 4 of 4	ENSP00000301948.6	P51608-1
	MECP2	ENST00000630151.3	TSL:5	c.1081C>G	p.Pro361Ala	missense	Exon 4 of 4	ENSP00000486089.2	P51608-1

Frequencies

GnomAD3 genomes AF: 0.0000180 AC: 2 AN: 110886 Hom.: 0 Cov.: 22

Gnomad AFR AF: 0.00

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: 0.0000379

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000277 AC: 5 AN: 180727 AF XY: 0.0000301

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: 0.0000497

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000911 AC: 100 AN: 1097522 Hom.: 0 Cov.: 35 AF XY: 0.0000992 AC XY: 36 AN XY: 362982

African (AFR) AF: 0.0000758 AC: 2 AN: 26377

American (AMR) AF: 0.00 AC: 0 AN: 35164

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19347

East Asian (EAS) AF: 0.00 AC: 0 AN: 30196

South Asian (SAS) AF: 0.0000554 AC: 3 AN: 54107

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40443

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4094

European-Non Finnish (NFE) AF: 0.000107 AC: 90 AN: 841745

Other (OTH) AF: 0.000109 AC: 5 AN: 46049

GnomAD4 genome AF: 0.0000180 AC: 2 AN: 110886 Hom.: 0 Cov.: 22 AF XY: 0.0000302 AC XY: 1 AN XY: 33090

African (AFR) AF: 0.00 AC: 0 AN: 30431

American (AMR) AF: 0.00 AC: 0 AN: 10517

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2642

East Asian (EAS) AF: 0.00 AC: 0 AN: 3531

South Asian (SAS) AF: 0.00 AC: 0 AN: 2620

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5981

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

European-Non Finnish (NFE) AF: 0.0000379 AC: 2 AN: 52759

Other (OTH) AF: 0.00 AC: 0 AN: 1483

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000264

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	2	Rett syndrome (2)
-	1	-	Inborn genetic diseases (1)
-	-	1	MECP2-related disorder (1)
-	1	-	not specified (1)
-	-	1	Severe neonatal-onset encephalopathy with microcephaly (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.054
BayesDel_addAF	Benign	-0.054	T
BayesDel_noAF	Benign	-0.17
CADD	Benign	17
DANN	Benign	0.93
DEOGEN2	Benign	0.23	T
FATHMM_MKL	Benign	0.54	D
LIST_S2	Uncertain	0.89	D
M_CAP	Pathogenic	0.37	D
MetaRNN	Benign	0.18	T
MetaSVM	Benign	-0.52	T
MutationAssessor	Benign	1.4	L
PhyloP100		1.5
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-0.080	N
REVEL	Uncertain	0.37
Sift	Benign	0.039	D
Sift4G	Benign	0.10	T
Varity_R		0.056
gMVP		0.66
Mutation Taster		=95/5	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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs61752373;

hg19: chrX-153296198;