rs267608402

Variant names:

• chrX-154030650-G-A
• rs267608402
• NM_001110792.2:c.1214C>T

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.Pro393Leu variant in MECP2 (NM_004992.4) is observed in at least 2 unaffected individuals (internal database - Ambry, internal database - Invitae) (BS2). The p.Pro393Leu variant is found in a patient with an alternate molecular basis of disease (internal database - Ambry) (BP5). The highest population minor allele frequency of the p.Pro393Leu variant in MECP2 in gnomAD v4.1 is 0.00002210 in Admixed American population (not sufficient to meet BS1 criteria). In summary, the p.Pro393Leu variant in MECP2 is classified as Likely Benign based on the ACMG/AMP criteria (BS2, BP5). LINK:https://erepo.genome.network/evrepo/ui/classification/CA232923/MONDO:0010726/036

• Frequency:
  • Genomes: 𝑓 0.0000094 (0 hom., 0 hem., cov: 19)
  • Exomes 𝑓: 9.2e-7 (0 hom. 0 hem.)
  • Failed GnomAD Quality Control
• Consequence: MECP2 NM_001110792.2 missense
• Clinical Significance: Likely benign reviewed by expert panel U:2 B:2 O:1
• Conservation: PhyloP100: 3.38
• 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 -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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MECP2	NM_001110792.2	MANE Select	c.1214C>T	p.Pro405Leu	missense	Exon 3 of 3	NP_001104262.1	A0A140VKC4
	MECP2	NM_004992.4	MANE Plus Clinical	c.1178C>T	p.Pro393Leu	missense	Exon 4 of 4	NP_004983.1	D3YJ43
	MECP2	NM_001316337.2		c.899C>T	p.Pro300Leu	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.1214C>T	p.Pro405Leu	missense	Exon 3 of 3	ENSP00000395535.2	P51608-2
	MECP2	ENST00000303391.11	TSL:1 MANE Plus Clinical	c.1178C>T	p.Pro393Leu	missense	Exon 4 of 4	ENSP00000301948.6	P51608-1
	MECP2	ENST00000630151.3	TSL:5	c.1178C>T	p.Pro393Leu	missense	Exon 4 of 4	ENSP00000486089.2	P51608-1

Frequencies

GnomAD3 genomes AF: 0.00000941 AC: 1 AN: 106288 Hom.: 0 Cov.: 19

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000994

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: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 9.16e-7 AC: 1 AN: 1091695 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 359509

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 26350

American (AMR) AF: 0.00 AC: 0 AN: 35193

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19371

East Asian (EAS) AF: 0.00 AC: 0 AN: 30188

South Asian (SAS) AF: 0.00 AC: 0 AN: 54077

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 36281

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3726

European-Non Finnish (NFE) AF: 0.00000119 AC: 1 AN: 840554

Other (OTH) AF: 0.00 AC: 0 AN: 45955

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000941 AC: 1 AN: 106288 Hom.: 0 Cov.: 19 AF XY: 0.00 AC XY: 0 AN XY: 28742

African (AFR) AF: 0.00 AC: 0 AN: 28954

American (AMR) AF: 0.0000994 AC: 1 AN: 10060

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2565

East Asian (EAS) AF: 0.00 AC: 0 AN: 3399

South Asian (SAS) AF: 0.00 AC: 0 AN: 2286

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5674

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 51055

Other (OTH) AF: 0.00 AC: 0 AN: 1399

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: reviewed by expert panel

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.060
CADD	Benign	21
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.48	T
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.94	D
M_CAP	Pathogenic	0.31	D
MetaRNN	Benign	0.23	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	1.0	L
PhyloP100		3.4
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-0.48	N
REVEL	Uncertain	0.38
Sift	Uncertain	0.014	D
Sift4G	Uncertain	0.047	D
Polyphen		0.26	B
Vest4		0.20
MutPred		0.32		Loss of glycosylation at P393 (P = 0.0102)
MVP		0.94
ClinPred		0.32	T
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.11
gMVP		0.45
Mutation Taster		=85/15	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: rs267608402; hg19: chrX-153296101; COSMIC: COSV106467800; COSMIC: COSV106467800;