rs61752387

Variant names:

• chrX-154030702-G-A
• rs61752387
• NM_001110792.2:c.1162C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BS2 BA1

This summary comes from the ClinGen Evidence Repository: The allele frequency of the c.1126C>T, p.(Pro376Ser) variant in MECP2(NM_004992.4) is 0.13% in European (Non-Finnish) sub population in gnomAD, which is high enough to be classified as benign based on thresholds defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like conditions (BA1). The p.(Pro376Ser) variant is observed in at least 2 unaffected individuals (PMID 10944854, PMID 14560307, RettBASE) (BS1). In summary, the p.(Pro376Ser) variant in MECP2 is classified as Benign based on the ACMG/AMP criteria applied (BA1, BS2). LINK:https://erepo.genome.network/evrepo/ui/classification/CA148292/MONDO:0010726/016

• Frequency:
  • Genomes: 𝑓 0.0010 (0 hom., 24 hem., cov: 22)
  • Exomes 𝑓: 0.0015 (0 hom. 537 hem.)
• Consequence: MECP2 NM_001110792.2 missense
• Clinical Significance: Benign reviewed by expert panel U:1 B:15
• Conservation: PhyloP100: 1.76
• Publications: 16 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: Benign. The variant received -12 ACMG points.

• BS2: For more information check the summary or visit ClinGen Evidence Repository.
• BA1: 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.1162C>T	p.Pro388Ser	missense	Exon 3 of 3	NP_001104262.1	A0A140VKC4
	MECP2	NM_004992.4	MANE Plus Clinical	c.1126C>T	p.Pro376Ser	missense	Exon 4 of 4	NP_004983.1	D3YJ43
	MECP2	NM_001316337.2		c.847C>T	p.Pro283Ser	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.1162C>T	p.Pro388Ser	missense	Exon 3 of 3	ENSP00000395535.2	P51608-2
	MECP2	ENST00000303391.11	TSL:1 MANE Plus Clinical	c.1126C>T	p.Pro376Ser	missense	Exon 4 of 4	ENSP00000301948.6	P51608-1
	MECP2	ENST00000630151.3	TSL:5	c.1126C>T	p.Pro376Ser	missense	Exon 4 of 4	ENSP00000486089.2	P51608-1

Frequencies

GnomAD3 genomes AF: 0.00102 AC: 112 AN: 109987 Hom.: 0 Cov.: 22

Gnomad AFR AF: 0.000596

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000192

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00172

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000335

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00160

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000998 AC: 176 AN: 176306 AF XY: 0.000976

Gnomad AFR exome AF: 0.000495

Gnomad AMR exome AF: 0.000110

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00292

Gnomad FIN exome AF: 0.000813

Gnomad NFE exome AF: 0.00134

Gnomad OTH exome AF: 0.00115

GnomAD4 exome AF: 0.00152 AC: 1661 AN: 1094648 Hom.: 0 Cov.: 35 AF XY: 0.00149 AC XY: 537 AN XY: 360858

African (AFR) AF: 0.000418 AC: 11 AN: 26285

American (AMR) AF: 0.0000855 AC: 3 AN: 35076

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19312

East Asian (EAS) AF: 0.00196 AC: 59 AN: 30169

South Asian (SAS) AF: 0.000148 AC: 8 AN: 53972

European-Finnish (FIN) AF: 0.000609 AC: 24 AN: 39441

Middle Eastern (MID) AF: 0.000522 AC: 2 AN: 3833

European-Non Finnish (NFE) AF: 0.00176 AC: 1479 AN: 840634

Other (OTH) AF: 0.00163 AC: 75 AN: 45926

GnomAD4 genome AF: 0.00102 AC: 112 AN: 110036 Hom.: 0 Cov.: 22 AF XY: 0.000744 AC XY: 24 AN XY: 32268

African (AFR) AF: 0.000595 AC: 18 AN: 30266

American (AMR) AF: 0.000192 AC: 2 AN: 10440

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2612

East Asian (EAS) AF: 0.00172 AC: 6 AN: 3482

South Asian (SAS) AF: 0.00 AC: 0 AN: 2501

European-Finnish (FIN) AF: 0.000335 AC: 2 AN: 5963

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 218

European-Non Finnish (NFE) AF: 0.00160 AC: 84 AN: 52374

Other (OTH) AF: 0.00 AC: 0 AN: 1498

Alfa AF: 0.00157 Hom.: 58

Bravo AF: 0.000929

TwinsUK AF: 0.00135 AC: 5

ALSPAC AF: 0.00138 AC: 4

ESP6500AA AF: 0.00107 AC: 4

ESP6500EA AF: 0.00152 AC: 10

ExAC AF: 0.000776 AC: 94

ClinVar

ClinVar submissions

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	10	not specified (10)
-	1	3	Rett syndrome (4)
-	-	1	Inborn genetic diseases (1)
-	-	1	Severe neonatal-onset encephalopathy with microcephaly (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.16
CADD	Benign	17
DANN	Benign	0.72
DEOGEN2	Benign	0.25	T
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Benign	0.78	T
M_CAP	Pathogenic	0.42	D
MetaRNN	Benign	0.012	T
MetaSVM	Benign	-0.63	T
MutationAssessor	Benign	0.0	N
PhyloP100		1.8
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-0.070	N
REVEL	Uncertain	0.51
Sift	Benign	0.20	T
Sift4G	Benign	0.073	T
Polyphen		0.0	B
Vest4		0.063
MVP		0.76
ClinPred		0.00039	T
GERP RS		3.2
Varity_R		0.042
gMVP		0.30
Mutation Taster		=98/2	polymorphism (auto)

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: rs61752387; hg19: chrX-153296153; COSMIC: COSV99066745; COSMIC: COSV99066745;