rs61752981

Variant names:

• chrX-154030687-G-A
• rs61752981
• NM_001110792.2:c.1177C>T

Your query was ambiguous. Multiple possible variants found:

• chrX-154030687-G-A
• chrX-154030687-G-C

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BS2 BP5

This summary comes from the ClinGen Evidence Repository: The p.Pro381Ser variant in MECP2 (NM_004992.4) is observed in at least 19 unaffected individuals (internal database - GeneDx, internal database - Invitae) (BS2). The p.Pro381Ser variant is found in a patient with an alternate molecular basis of disease (internal database - GeneDx) (BP5). The highest population minor allele frequency of the p.Pro381Ser variant in MECP2 in gnomAD v4.1 is 0.00003574 in the African/African American population (not sufficient to meet BS1 criteria). In summary, the p.Pro381Ser variant in MECP2 is classified as Likely Benign based on the ACMG/AMP criteria (BS2, BP5). LINK:https://erepo.genome.network/evrepo/ui/classification/CA10558497/MONDO:0010726/036

• Frequency:
  • Genomes: 𝑓 0.000037 (0 hom., 1 hem., cov: 21)
  • Exomes 𝑓: 0.000020 (0 hom. 5 hem.)
• Consequence: MECP2 NM_001110792.2 missense
• Clinical Significance: Likely benign reviewed by expert panel U:3 B:2
• Conservation: PhyloP100: 2.14
• 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: Likely_benign. The variant received -5 ACMG points.

• BP5: 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MECP2	NM_001110792.2	MANE Select	c.1177C>T	p.Pro393Ser	missense	Exon 3 of 3	NP_001104262.1
	MECP2	NM_004992.4	MANE Plus Clinical	c.1141C>T	p.Pro381Ser	missense	Exon 4 of 4	NP_004983.1
	MECP2	NM_001316337.2		c.862C>T	p.Pro288Ser	missense	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.1177C>T	p.Pro393Ser	missense	Exon 3 of 3	ENSP00000395535.2
	MECP2	ENST00000303391.11	TSL:1 MANE Plus Clinical	c.1141C>T	p.Pro381Ser	missense	Exon 4 of 4	ENSP00000301948.6
	MECP2	ENST00000630151.3	TSL:5	c.1141C>T	p.Pro381Ser	missense	Exon 4 of 4	ENSP00000486089.2

Frequencies

GnomAD3 genomes AF: 0.0000369 AC: 4 AN: 108526 Hom.: 0 Cov.: 21

Gnomad AFR AF: 0.0000337

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: 0.0000577

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000577 AC: 1 AN: 173418 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000130

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000201 AC: 22 AN: 1091856 Hom.: 0 Cov.: 35 AF XY: 0.0000139 AC XY: 5 AN XY: 359010

African (AFR) AF: 0.0000381 AC: 1 AN: 26269

American (AMR) AF: 0.00 AC: 0 AN: 35042

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19287

East Asian (EAS) AF: 0.00 AC: 0 AN: 30167

South Asian (SAS) AF: 0.00 AC: 0 AN: 53884

European-Finnish (FIN) AF: 0.0000263 AC: 1 AN: 38032

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3648

European-Non Finnish (NFE) AF: 0.0000238 AC: 20 AN: 839666

Other (OTH) AF: 0.00 AC: 0 AN: 45861

GnomAD4 genome AF: 0.0000369 AC: 4 AN: 108526 Hom.: 0 Cov.: 21 AF XY: 0.0000324 AC XY: 1 AN XY: 30870

African (AFR) AF: 0.0000337 AC: 1 AN: 29692

American (AMR) AF: 0.00 AC: 0 AN: 10278

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2599

East Asian (EAS) AF: 0.00 AC: 0 AN: 3446

South Asian (SAS) AF: 0.00 AC: 0 AN: 2448

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5741

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

European-Non Finnish (NFE) AF: 0.0000577 AC: 3 AN: 51957

Other (OTH) AF: 0.00 AC: 0 AN: 1452

Alfa AF: 0.000142 Hom.: 1

Bravo AF: 0.0000151

ExAC AF: 0.00000826 AC: 1

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: reviewed by expert panel

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.072
BayesDel_addAF	Benign	-0.00097	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	11
DANN	Benign	0.26
DEOGEN2	Benign	0.23	T
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Benign	0.83	T
M_CAP	Pathogenic	0.69	D
MetaRNN	Benign	0.34	T
MetaSVM	Benign	-0.40	T
MutationAssessor	Benign	0.0	N
PhyloP100		2.1
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	0.65	N
REVEL	Uncertain	0.45
Sift	Benign	0.10	T
Sift4G	Benign	0.37	T
Polyphen		0.32	B
Vest4		0.19
MutPred		0.27		Gain of phosphorylation at P381 (P = 0.0062)
MVP		0.62
ClinPred		0.11	T
GERP RS		3.8
Varity_R		0.047
gMVP		0.38
Mutation Taster		=92/8	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: rs61752981; hg19: chrX-153296138;