rs63485860

Variant names:

• chrX-154031211-C-G
• rs63485860
• NM_001110792.2:c.653G>C

Your query was ambiguous. Multiple possible variants found:

• chrX-154031211-C-G
• chrX-154031211-C-T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BS1 BP5_Strong BS2

This summary comes from the ClinGen Evidence Repository: The allele frequency of the p.Gly206Ala variant in MECP2 (NM_004992.3) is 0.008% in the European (non-Finnish) sub population in gnomAD, which is high enough to meet the BS1 criteria based on thresholds defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like conditions (BS1). The p.Gly206Ala variant in MECP2 is observed in at least 2 unaffected individuals (PMID 17427193, internal database - GeneDx) (BS2). The p.Gly206Ala variant is found in at least 3 patients with an alternate molecular basis of disease (internal database - GeneDx; internal database - Invitae) (BP5_strong). In summary, the p.Gly206Ala variant in MECP2 is classified as Benign based on the ACMG/AMP criteria (BS1, BS2, BP5_strong). LINK:https://erepo.genome.network/evrepo/ui/classification/CA170346/MONDO:0010726/016

• Frequency:
  • Genomes: 𝑓 0.000081 (0 hom., 3 hem., cov: 23)
  • Exomes 𝑓: 0.000087 (0 hom. 26 hem.)
• Consequence: MECP2 ENST00000453960.7 missense
• Clinical Significance: Benign reviewed by expert panel U:1 B:7
• Conservation: PhyloP100: 3.65
• Publications: 3 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: Benign. The variant received -12 ACMG points.

• BP5: For more information check the summary or visit ClinGen Evidence Repository.
• BS1: 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: ENST00000453960.7. 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.653G>C	p.Gly218Ala	missense	Exon 3 of 3	NP_001104262.1
	MECP2	NM_004992.4	MANE Plus Clinical	c.617G>C	p.Gly206Ala	missense	Exon 4 of 4	NP_004983.1
	MECP2	NM_001386137.1		c.-53G>C		5_prime_UTR_premature_start_codon_gain	Exon 6 of 6	NP_001373066.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MECP2	ENST00000453960.7	TSL:1 MANE Select	c.653G>C	p.Gly218Ala	missense	Exon 3 of 3	ENSP00000395535.2
	MECP2	ENST00000303391.11	TSL:1 MANE Plus Clinical	c.617G>C	p.Gly206Ala	missense	Exon 4 of 4	ENSP00000301948.6
	MECP2	ENST00000630151.3	TSL:5	c.617G>C	p.Gly206Ala	missense	Exon 4 of 4	ENSP00000486089.2

Frequencies

GnomAD3 genomes AF: 0.0000811 AC: 9 AN: 110910 Hom.: 0 Cov.: 23

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: 0.000171

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000218 AC: 4 AN: 183510 AF XY: 0.0000147

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000365

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000366

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000874 AC: 96 AN: 1098263 Hom.: 0 Cov.: 35 AF XY: 0.0000715 AC XY: 26 AN XY: 363621

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

American (AMR) AF: 0.0000284 AC: 1 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: 40532

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

European-Non Finnish (NFE) AF: 0.000112 AC: 94 AN: 842145

Other (OTH) AF: 0.0000217 AC: 1 AN: 46098

GnomAD4 genome AF: 0.0000811 AC: 9 AN: 110910 Hom.: 0 Cov.: 23 AF XY: 0.0000907 AC XY: 3 AN XY: 33090

African (AFR) AF: 0.00 AC: 0 AN: 30403

American (AMR) AF: 0.00 AC: 0 AN: 10574

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2628

East Asian (EAS) AF: 0.00 AC: 0 AN: 3519

South Asian (SAS) AF: 0.00 AC: 0 AN: 2525

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6087

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 238

European-Non Finnish (NFE) AF: 0.000171 AC: 9 AN: 52771

Other (OTH) AF: 0.00 AC: 0 AN: 1485

Alfa AF: 0.000214 Hom.: 1

Bravo AF: 0.0000642

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	2	Rett syndrome (2)
-	1	-	Autism, susceptibility to, X-linked 3 (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	0.18
BayesDel_addAF	Pathogenic	0.50	D
BayesDel_noAF	Pathogenic	0.59
CADD	Benign	23
DANN	Benign	0.51
DEOGEN2	Uncertain	0.57	D
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D
M_CAP	Pathogenic	0.77	D
MetaRNN	Uncertain	0.58	D
MetaSVM	Pathogenic	0.81	D
MutationAssessor	Uncertain	2.3	M
PhyloP100		3.7
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-1.5	N
REVEL	Pathogenic	0.74
Sift	Uncertain	0.0040	D
Sift4G	Benign	0.34	T
Polyphen		1.0	D
Vest4		0.46
MVP		1.0
ClinPred		0.33	T
GERP RS		5.5
Varity_R		0.51
gMVP		0.85
Mutation Taster		=35/65	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: rs63485860; hg19: chrX-153296662;