rs781816931

Variant names:

• chrX-154030640-G-A
• rs781816931
• NM_001110792.2:c.1224C>T

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BS2_Supporting BA1

This summary comes from the ClinGen Evidence Repository: The allele frequency of the p.Ser396= variant in MECP2 (NM_004992.3) is 0.15% in European (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.Ser396= variant is observed in 1 unaffected individual (internal database) (BS2_supporting). In summary, the p.Ser396= variant in MECP2 is classified as Benign based on the ACMG/AMP criteria (BA1, BS2_supporting). LINK:https://erepo.genome.network/evrepo/ui/classification/CA207604/MONDO:0010726/016

• Frequency:
  • Genomes: 𝑓 0.00020 (0 hom., 9 hem., cov: 20)
  • Exomes 𝑓: 0.00027 (0 hom. 100 hem.)
• Consequence: MECP2 NM_001110792.2 synonymous
• Clinical Significance: Benign reviewed by expert panel U:1 B:8
• Conservation: PhyloP100: 0.490
• Publications: 1 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 -9 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MECP2	NM_001110792.2	MANE Select	c.1224C>T	p.Ser408Ser	synonymous	Exon 3 of 3	NP_001104262.1
	MECP2	NM_004992.4	MANE Plus Clinical	c.1188C>T	p.Ser396Ser	synonymous	Exon 4 of 4	NP_004983.1
	MECP2	NM_001316337.2		c.909C>T	p.Ser303Ser	synonymous	Exon 5 of 5	NP_001303266.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MECP2	ENST00000453960.7	TSL:1 MANE Select	c.1224C>T	p.Ser408Ser	synonymous	Exon 3 of 3	ENSP00000395535.2
	MECP2	ENST00000303391.11	TSL:1 MANE Plus Clinical	c.1188C>T	p.Ser396Ser	synonymous	Exon 4 of 4	ENSP00000301948.6
	MECP2	ENST00000630151.3	TSL:5	c.1188C>T	p.Ser396Ser	synonymous	Exon 4 of 4	ENSP00000486089.2

Frequencies

GnomAD3 genomes AF: 0.000196 AC: 21 AN: 107298 Hom.: 0 Cov.: 20

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000197

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00121

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000233

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000281 AC: 49 AN: 174480 AF XY: 0.000328

Gnomad AFR exome AF: 0.0000845

Gnomad AMR exome AF: 0.000146

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000728

Gnomad FIN exome AF: 0.00148

Gnomad NFE exome AF: 0.000308

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000269 AC: 294 AN: 1092401 Hom.: 0 Cov.: 33 AF XY: 0.000278 AC XY: 100 AN XY: 360117

African (AFR) AF: 0.0000379 AC: 1 AN: 26372

American (AMR) AF: 0.000114 AC: 4 AN: 35198

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19374

East Asian (EAS) AF: 0.0000662 AC: 2 AN: 30191

South Asian (SAS) AF: 0.0000370 AC: 2 AN: 54095

European-Finnish (FIN) AF: 0.00135 AC: 49 AN: 36235

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3800

European-Non Finnish (NFE) AF: 0.000275 AC: 231 AN: 841157

Other (OTH) AF: 0.000109 AC: 5 AN: 45979

GnomAD4 genome AF: 0.000196 AC: 21 AN: 107298 Hom.: 0 Cov.: 20 AF XY: 0.000303 AC XY: 9 AN XY: 29736

African (AFR) AF: 0.00 AC: 0 AN: 29260

American (AMR) AF: 0.000197 AC: 2 AN: 10163

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2577

East Asian (EAS) AF: 0.00 AC: 0 AN: 3419

South Asian (SAS) AF: 0.00 AC: 0 AN: 2355

European-Finnish (FIN) AF: 0.00121 AC: 7 AN: 5784

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 235

European-Non Finnish (NFE) AF: 0.000233 AC: 12 AN: 51411

Other (OTH) AF: 0.00 AC: 0 AN: 1429

Alfa AF: 0.000270 Hom.: 2

Bravo AF: 0.000170

ExAC AF: 0.000363 AC: 44

EpiCase AF: 0.000273

EpiControl AF: 0.000830

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: reviewed by expert panel

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_noAF	Benign	-0.52
CADD	Benign	0.85
DANN	Benign	0.65
DEOGEN2	Benign	0.070	T
FATHMM_MKL	Benign	0.67	D
LIST_S2	Benign	0.35	T
MetaRNN	Benign	0.013	T
MetaSVM	Benign	-0.86	T
PhyloP100		0.49
GERP RS		1.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	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: rs781816931; hg19: chrX-153296091; COSMIC: COSV100318075; COSMIC: COSV100318075;