rs141382970

Variant names:

• chrX-154031080-G-A
• rs141382970
• NM_001110792.2:c.784C>T

Your query was ambiguous. Multiple possible variants found:

• chrX-154031080-G-A
• chrX-154031080-G-C

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

This summary comes from the ClinGen Evidence Repository: The c.748C>T p.Arg250Cys variant in MECP2 (NM_004992.3) is present in 1 XY and 4 XX individuals in gnomAD (0.0034% in the European non-Finnish population) (not sufficient to meet BS1 criteria). The p.Arg250Cys variant is observed in at least 2 unaffected individuals (GeneDx internal data) (BS2). The p.Arg250Cys variant has been observed in at least 1 individual with RTT-like disease (PMID 30405208); however PS4 cannot be applied at any strength due to the gnomAD frequency. Computational prediction analysis tools are inconclusive for this variant (criteria not met). Alternative missense variants (p.Arg250Gly and p.Arg250His) have previously been identified within this codon, however they are not considered to be pathogenic variants (PMID 30405208; RettBASE: RettSyndrome.org Variation Database mecp2.chw.edu.au). In the absence of conflicting evidence, this is sufficient evidence to classify as likely benign based on the specifications defined by the ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel. In summary, the c.748C>T p.Arg250Cys variant in MECP2 is classified as Likely Benign based on the ACMG/AMP criteria (BS2). LINK:https://erepo.genome.network/evrepo/ui/classification/CA205183/MONDO:0010726/036

• Frequency:
  • Genomes: 𝑓 0.0000089 (0 hom., 1 hem., cov: 23)
  • Exomes 𝑓: 0.000047 (0 hom. 21 hem.)
• Consequence: MECP2 NM_001110792.2 missense
• Clinical Significance: Likely benign reviewed by expert panel U:4 B:3
• Conservation: PhyloP100: 4.93
• Publications: 5 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: Likely_benign. The variant received -4 ACMG points.

• 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.784C>T	p.Arg262Cys	missense	Exon 3 of 3	NP_001104262.1	A0A140VKC4
	MECP2	NM_004992.4	MANE Plus Clinical	c.748C>T	p.Arg250Cys	missense	Exon 4 of 4	NP_004983.1	D3YJ43
	MECP2	NM_001316337.2		c.469C>T	p.Arg157Cys	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.784C>T	p.Arg262Cys	missense	Exon 3 of 3	ENSP00000395535.2	P51608-2
	MECP2	ENST00000303391.11	TSL:1 MANE Plus Clinical	c.748C>T	p.Arg250Cys	missense	Exon 4 of 4	ENSP00000301948.6	P51608-1
	MECP2	ENST00000630151.3	TSL:5	c.748C>T	p.Arg250Cys	missense	Exon 4 of 4	ENSP00000486089.2	P51608-1

Frequencies

GnomAD3 genomes AF: 0.00000887 AC: 1 AN: 112767 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: 0.0000188

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000273 AC: 5 AN: 182990 AF XY: 0.0000148

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: 0.0000625

Gnomad NFE exome AF: 0.0000368

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000474 AC: 52 AN: 1098086 Hom.: 0 Cov.: 35 AF XY: 0.0000578 AC XY: 21 AN XY: 363450

African (AFR) AF: 0.0000379 AC: 1 AN: 26398

American (AMR) AF: 0.0000284 AC: 1 AN: 35202

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19385

East Asian (EAS) AF: 0.00 AC: 0 AN: 30202

South Asian (SAS) AF: 0.0000369 AC: 2 AN: 54142

European-Finnish (FIN) AF: 0.0000247 AC: 1 AN: 40523

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4136

European-Non Finnish (NFE) AF: 0.0000523 AC: 44 AN: 842006

Other (OTH) AF: 0.0000651 AC: 3 AN: 46092

GnomAD4 genome AF: 0.00000887 AC: 1 AN: 112767 Hom.: 0 Cov.: 23 AF XY: 0.0000286 AC XY: 1 AN XY: 34911

African (AFR) AF: 0.00 AC: 0 AN: 31035

American (AMR) AF: 0.00 AC: 0 AN: 10783

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2649

East Asian (EAS) AF: 0.00 AC: 0 AN: 3565

South Asian (SAS) AF: 0.00 AC: 0 AN: 2773

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6259

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 239

European-Non Finnish (NFE) AF: 0.0000188 AC: 1 AN: 53254

Other (OTH) AF: 0.00 AC: 0 AN: 1521

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000453

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000149 AC: 1

ExAC AF: 0.0000247 AC: 3

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	2	1	not provided (3)
-	1	-	MECP2-related disorder (1)
-	-	1	not specified (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	Pathogenic	0.88
BayesDel_addAF	Pathogenic	0.45	D
BayesDel_noAF	Pathogenic	0.52
CADD	Uncertain	25
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.70	D
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.97	D
M_CAP	Pathogenic	0.93	D
MetaRNN	Uncertain	0.73	D
MetaSVM	Uncertain	0.77	D
MutationAssessor	Uncertain	2.3	M
PhyloP100		4.9
PrimateAI	Pathogenic	0.88	D
PROVEAN	Uncertain	-3.5	D
REVEL	Pathogenic	0.65
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.011	D
Polyphen		1.0	D
Vest4		0.66
MVP		1.0
ClinPred		0.61	D
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.69
gMVP		0.96
Mutation Taster		=88/12	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs141382970; hg19: chrX-153296531;