rs61753971

Variant names:

• chrX-154030546-C-T
• rs61753971
• NM_001110792.2:c.1318G>A

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BS1 BS2

This summary comes from the ClinGen Evidence Repository: The allele frequency of the p.Gly428Ser (NM_004992) variant in MECP2 is 0.014% in gnomAD, which is high enough to meet BS1 criteria based on thresholds defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like conditions (BS1). The p.Gly428Ser variant is observed in at least 2 unaffected individuals (PMID:11238684, PMID:12161600) (BS2). In summary the p.Gly428Ser variant in MECP2 is classified as Benign for Rett Syndrome based on the ACMG/AMP criteria (BS1, BS2). LINK:https://erepo.genome.network/evrepo/ui/classification/CA121707/MONDO:0010726/016

• Frequency:
  • Genomes: 𝑓 0.000099 (0 hom., 5 hem., cov: 22)
  • Exomes 𝑓: 0.000061 (0 hom. 23 hem.)
• Consequence: MECP2 NM_001110792.2 missense
• Clinical Significance: Benign reviewed by expert panel P:1 B:8
• Conservation: PhyloP100: 2.49
• Publications: 9 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

Specifications for MECP2 are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Benign. The variant received -8 ACMG points.

• 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: 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.1318G>A	p.Gly440Ser	missense	Exon 3 of 3	NP_001104262.1	A0A140VKC4
	MECP2	NM_004992.4	MANE Plus Clinical	c.1282G>A	p.Gly428Ser	missense	Exon 4 of 4	NP_004983.1	D3YJ43
	MECP2	NM_001316337.2		c.1003G>A	p.Gly335Ser	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.1318G>A	p.Gly440Ser	missense	Exon 3 of 3	ENSP00000395535.2	P51608-2
	MECP2	ENST00000303391.11	TSL:1 MANE Plus Clinical	c.1282G>A	p.Gly428Ser	missense	Exon 4 of 4	ENSP00000301948.6	P51608-1
	MECP2	ENST00000630151.3	TSL:5	c.1282G>A	p.Gly428Ser	missense	Exon 4 of 4	ENSP00000486089.2	P51608-1

Frequencies

GnomAD3 genomes AF: 0.0000993 AC: 11 AN: 110805 Hom.: 0 Cov.: 22

Gnomad AFR AF: 0.0000658

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000957

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000167

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000133

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000131 AC: 24 AN: 182729 AF XY: 0.000134

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000182

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000722

Gnomad FIN exome AF: 0.0000642

Gnomad NFE exome AF: 0.000122

Gnomad OTH exome AF: 0.000221

GnomAD4 exome AF: 0.0000610 AC: 67 AN: 1097691 Hom.: 0 Cov.: 32 AF XY: 0.0000633 AC XY: 23 AN XY: 363127

African (AFR) AF: 0.00 AC: 0 AN: 26397

American (AMR) AF: 0.000227 AC: 8 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: 0.000111 AC: 6 AN: 54144

European-Finnish (FIN) AF: 0.0000998 AC: 4 AN: 40095

Middle Eastern (MID) AF: 0.000968 AC: 4 AN: 4132

European-Non Finnish (NFE) AF: 0.0000534 AC: 45 AN: 842028

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

GnomAD4 genome AF: 0.0000993 AC: 11 AN: 110805 Hom.: 0 Cov.: 22 AF XY: 0.000151 AC XY: 5 AN XY: 33021

African (AFR) AF: 0.0000658 AC: 2 AN: 30416

American (AMR) AF: 0.0000957 AC: 1 AN: 10453

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2637

East Asian (EAS) AF: 0.00 AC: 0 AN: 3529

South Asian (SAS) AF: 0.00 AC: 0 AN: 2587

European-Finnish (FIN) AF: 0.000167 AC: 1 AN: 5989

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 236

European-Non Finnish (NFE) AF: 0.000133 AC: 7 AN: 52791

Other (OTH) AF: 0.00 AC: 0 AN: 1492

Alfa AF: 0.000132 Hom.: 2

Bravo AF: 0.0000756

ExAC AF: 0.000124 AC: 15

ClinVar

ClinVar submissions

Significance: Benign

Revision: reviewed by expert panel

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.090
BayesDel_addAF	Uncertain	0.064	T
BayesDel_noAF	Pathogenic	0.16
CADD	Benign	18
DANN	Benign	0.96
DEOGEN2	Benign	0.26	T
FATHMM_MKL	Benign	0.73	D
LIST_S2	Uncertain	0.90	D
M_CAP	Pathogenic	0.38	D
MetaRNN	Benign	0.23	T
MetaSVM	Uncertain	-0.093	T
MutationAssessor	Benign	0.46	N
PhyloP100		2.5
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-0.020	N
REVEL	Uncertain	0.45
Sift	Uncertain	0.0050	D
Sift4G	Benign	0.44	T
Polyphen		0.96	D
Vest4		0.13
MVP		1.0
ClinPred		0.057	T
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Varity_R		0.20
gMVP		0.14
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

Other links and lift over

dbSNP: rs61753971; hg19: chrX-153295997;