X-154030695-G-C

Variant names:

• chrX-154030695-G-C
• rs201314910
• NM_001110792.2:c.1169C>G

Variant summary

Our verdict is Uncertain significance. The variant received -2 ACMG points: 2P and 4B. BS2 PS4_Moderate

This summary comes from the ClinGen Evidence Repository: The p.Ala378Gly variant has been observed in 3 individuals with Rett syndrome (PMID 16473305, 20031356, 11960578) (PS4_moderate). The p.Ala378Gly variant is observed in at least 7 unaffected individuals (internal database - GeneDx; internal database - Invitae) (BS2). The p.Ala378Gly variant in MECP2 is present in 3 female and 1 male individual(s) in gnomAD (0.002%) (not sufficient to meet BS1 criteria). In summary, the p.Ala378Gly variant in MECP2 is classified as a Variant of Uncertain Significance based on the ACMG/AMP criteria (BS2, PS4_moderate). LINK:https://erepo.genome.network/evrepo/ui/classification/CA270202/MONDO:0010726/036

• Frequency:
  • Genomes: 𝑓 0.000027 (0 hom., 0 hem., cov: 22)
  • Exomes 𝑓: 0.0000064 (0 hom. 3 hem.)
• Consequence: MECP2 NM_001110792.2 missense
• Clinical Significance: Likely benign reviewed by expert panel U:6 B:3
• Conservation: PhyloP100: 2.85
• Publications: 11 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), ClinGen, Ambry Genetics, Orphanet, 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 -2 ACMG points.

• PS4: 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.1169C>G	p.Ala390Gly	missense	Exon 3 of 3	NP_001104262.1	A0A140VKC4
	MECP2	NM_004992.4	MANE Plus Clinical	c.1133C>G	p.Ala378Gly	missense	Exon 4 of 4	NP_004983.1	D3YJ43
	MECP2	NM_001316337.2		c.854C>G	p.Ala285Gly	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.1169C>G	p.Ala390Gly	missense	Exon 3 of 3	ENSP00000395535.2	P51608-2
	MECP2	ENST00000303391.11	TSL:1 MANE Plus Clinical	c.1133C>G	p.Ala378Gly	missense	Exon 4 of 4	ENSP00000301948.6	P51608-1
	MECP2	ENST00000630151.3	TSL:5	c.1133C>G	p.Ala378Gly	missense	Exon 4 of 4	ENSP00000486089.2	P51608-1

Frequencies

GnomAD3 genomes AF: 0.0000274 AC: 3 AN: 109524 Hom.: 0 Cov.: 22

Gnomad AFR AF: 0.0000333

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000966

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: 0.0000191

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000172 AC: 3 AN: 174908 AF XY: 0.0000159

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000737

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000697

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000640 AC: 7 AN: 1093136 Hom.: 0 Cov.: 35 AF XY: 0.00000834 AC XY: 3 AN XY: 359746

African (AFR) AF: 0.0000381 AC: 1 AN: 26266

American (AMR) AF: 0.0000571 AC: 2 AN: 35043

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19296

East Asian (EAS) AF: 0.00 AC: 0 AN: 30157

South Asian (SAS) AF: 0.00 AC: 0 AN: 53895

European-Finnish (FIN) AF: 0.0000257 AC: 1 AN: 38887

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3764

European-Non Finnish (NFE) AF: 0.00000238 AC: 2 AN: 839963

Other (OTH) AF: 0.0000218 AC: 1 AN: 45865

GnomAD4 genome AF: 0.0000274 AC: 3 AN: 109568 Hom.: 0 Cov.: 22 AF XY: 0.00 AC XY: 0 AN XY: 31848

African (AFR) AF: 0.0000333 AC: 1 AN: 30069

American (AMR) AF: 0.0000964 AC: 1 AN: 10369

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2610

East Asian (EAS) AF: 0.00 AC: 0 AN: 3471

South Asian (SAS) AF: 0.00 AC: 0 AN: 2509

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5894

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 216

European-Non Finnish (NFE) AF: 0.0000191 AC: 1 AN: 52262

Other (OTH) AF: 0.00 AC: 0 AN: 1494

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ExAC AF: 0.0000165 AC: 2

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	3	1	Rett syndrome (4)
-	1	1	not provided (2)
-	1	-	Inborn genetic diseases (1)
-	1	-	MECP2-related disorder (1)
-	-	1	Severe neonatal-onset encephalopathy with microcephaly (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.088
BayesDel_addAF	Uncertain	0.077	D
BayesDel_noAF	Uncertain	0.070
CADD	Benign	16
DANN	Benign	0.91
DEOGEN2	Benign	0.25	T
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.88	D
M_CAP	Pathogenic	0.56	D
MetaRNN	Benign	0.26	T
MetaSVM	Uncertain	-0.089	T
MutationAssessor	Benign	0.0	N
PhyloP100		2.9
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-0.68	N
REVEL	Uncertain	0.55
Sift	Benign	0.17	T
Sift4G	Benign	0.39	T
Polyphen		0.63	P
Vest4		0.33
MVP		0.97
ClinPred		0.082	T
GERP RS		5.0
Varity_R		0.14
gMVP		0.32
Mutation Taster		=99/1	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: rs201314910; hg19: chrX-153296146;