rs782171742

Variant names:

• chrX-154030744-G-A
• rs782171742
• NM_001110792.2:c.1120C>T

Your query was ambiguous. Multiple possible variants found:

• chrX-154030744-G-A
• chrX-154030744-G-C
• chrX-154030744-G-T

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 p.Pro362Ser variant in MECP2 (NM_004992.3) is present in 1 XX and 1 XY individual in gnomAD (0.0011%) (not sufficient to meet BS1 criteria). The p.Pro362Ser variant in MECP2 is observed in at least 3 unaffected individuals (internal database - Invitae) (BS2). 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 p.Pro362Ser variant in MECP2 is classified as Likely Benign based on the ACMG/AMP criteria (BS2). LINK:https://erepo.genome.network/evrepo/ui/classification/CA415168068/MONDO:0010726/036

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 0.000017 (0 hom. 7 hem.)
• Consequence: MECP2 NM_001110792.2 missense
• Clinical Significance: Likely benign reviewed by expert panel U:1 B:3
• Conservation: PhyloP100: 4.86
• Publications: 3 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.1120C>T	p.Pro374Ser	missense	Exon 3 of 3	NP_001104262.1	A0A140VKC4
	MECP2	NM_004992.4	MANE Plus Clinical	c.1084C>T	p.Pro362Ser	missense	Exon 4 of 4	NP_004983.1	D3YJ43
	MECP2	NM_001316337.2		c.805C>T	p.Pro269Ser	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.1120C>T	p.Pro374Ser	missense	Exon 3 of 3	ENSP00000395535.2	P51608-2
	MECP2	ENST00000303391.11	TSL:1 MANE Plus Clinical	c.1084C>T	p.Pro362Ser	missense	Exon 4 of 4	ENSP00000301948.6	P51608-1
	MECP2	ENST00000630151.3	TSL:5	c.1084C>T	p.Pro362Ser	missense	Exon 4 of 4	ENSP00000486089.2	P51608-1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD2 exomes AF: 0.0000111 AC: 2 AN: 180544 AF XY: 0.0000151

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: 0.0000249

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000173 AC: 19 AN: 1097399 Hom.: 0 Cov.: 35 AF XY: 0.0000193 AC XY: 7 AN XY: 362895

African (AFR) AF: 0.00 AC: 0 AN: 26359

American (AMR) AF: 0.00 AC: 0 AN: 35147

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19346

East Asian (EAS) AF: 0.00 AC: 0 AN: 30192

South Asian (SAS) AF: 0.00 AC: 0 AN: 54111

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40428

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4095

European-Non Finnish (NFE) AF: 0.0000226 AC: 19 AN: 841684

Other (OTH) AF: 0.00 AC: 0 AN: 46037

GnomAD4 genome Cov.: 22

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

EpiCase AF: 0.0000545

EpiControl AF: 0.000119

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	1	Intellectual disability (1)
-	1	-	not provided (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	0.074
BayesDel_addAF	Uncertain	0.075	D
BayesDel_noAF	Uncertain	-0.080
CADD	Benign	19
DANN	Uncertain	0.98
DEOGEN2	Benign	0.23	T
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Uncertain	0.89	D
M_CAP	Pathogenic	0.39	D
MetaRNN	Benign	0.26	T
MetaSVM	Uncertain	-0.23	T
MutationAssessor	Benign	1.4	L
PhyloP100		4.9
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	0.020	N
REVEL	Uncertain	0.40
Sift	Uncertain	0.018	D
Sift4G	Benign	0.23	T
Polyphen		0.73	P
Vest4		0.12
MutPred		0.26		Gain of phosphorylation at P362 (P = 0.0047)
MVP		0.59
ClinPred		0.27	T
GERP RS		5.1
Varity_R		0.11
gMVP		0.60
Mutation Taster		=99/1	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: rs782171742; hg19: chrX-153296195; COSMIC: COSV57652398; COSMIC: COSV57652398;