rs797045691

Variant names:

• chrX-154030633-G-A
• rs797045691
• NM_001110792.2:c.1231C>T

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BS2_Supporting BS1

This summary comes from the ClinGen Evidence Repository: The allele frequency of the p.Pro399Ser variant in MECP2 (NM_004992.3) is 0.01% in Latino/Admixed American sub population in gnomAD, which is high enough to meet the BS1 criteria based on thresholds defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like conditions (BS1). The p.Pro399Ser variant is observed in 1 unaffected individual (internal database) (BS2_supporting). In summary, the p.Pro399Ser variant in MECP2 is classified as a Likely Benign based on the ACMG/AMP criteria (BS1, BS2_supporting). LINK:https://erepo.genome.network/evrepo/ui/classification/CA206184/MONDO:0010726/016

• Frequency:
  • Genomes: 𝑓 0.000037 (0 hom., 1 hem., cov: 20)
  • Exomes 𝑓: 0.000015 (0 hom. 2 hem.)
• Consequence: MECP2 NM_001110792.2 missense
• Clinical Significance: Likely benign reviewed by expert panel U:2 B:3
• Conservation: PhyloP100: 2.54
• 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.

• BS1: 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.1231C>T	p.Pro411Ser	missense	Exon 3 of 3	NP_001104262.1	A0A140VKC4
	MECP2	NM_004992.4	MANE Plus Clinical	c.1195C>T	p.Pro399Ser	missense	Exon 4 of 4	NP_004983.1	D3YJ43
	MECP2	NM_001316337.2		c.916C>T	p.Pro306Ser	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.1231C>T	p.Pro411Ser	missense	Exon 3 of 3	ENSP00000395535.2	P51608-2
	MECP2	ENST00000303391.11	TSL:1 MANE Plus Clinical	c.1195C>T	p.Pro399Ser	missense	Exon 4 of 4	ENSP00000301948.6	P51608-1
	MECP2	ENST00000630151.3	TSL:5	c.1195C>T	p.Pro399Ser	missense	Exon 4 of 4	ENSP00000486089.2	P51608-1

Frequencies

GnomAD3 genomes AF: 0.0000370 AC: 4 AN: 107981 Hom.: 0 Cov.: 20

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000983

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: 0.0000580

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000171 AC: 3 AN: 175912 AF XY: 0.0000311

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000366

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000254

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000146 AC: 16 AN: 1093362 Hom.: 0 Cov.: 33 AF XY: 0.00000554 AC XY: 2 AN XY: 360762

African (AFR) AF: 0.00 AC: 0 AN: 26384

American (AMR) AF: 0.0000284 AC: 1 AN: 35200

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19377

East Asian (EAS) AF: 0.00 AC: 0 AN: 30197

South Asian (SAS) AF: 0.00 AC: 0 AN: 54112

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 36614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3888

European-Non Finnish (NFE) AF: 0.0000178 AC: 15 AN: 841588

Other (OTH) AF: 0.00 AC: 0 AN: 46002

GnomAD4 genome AF: 0.0000370 AC: 4 AN: 107981 Hom.: 0 Cov.: 20 AF XY: 0.0000329 AC XY: 1 AN XY: 30351

African (AFR) AF: 0.00 AC: 0 AN: 29503

American (AMR) AF: 0.0000983 AC: 1 AN: 10174

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2592

East Asian (EAS) AF: 0.00 AC: 0 AN: 3452

South Asian (SAS) AF: 0.00 AC: 0 AN: 2415

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5824

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 236

European-Non Finnish (NFE) AF: 0.0000580 AC: 3 AN: 51687

Other (OTH) AF: 0.00 AC: 0 AN: 1434

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000302

EpiCase AF: 0.000109

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)
-	-	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	Benign	0.074
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	17
DANN	Benign	0.65
DEOGEN2	Benign	0.22	T
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.85	D
M_CAP	Pathogenic	0.45	D
MetaRNN	Benign	0.097	T
MetaSVM	Benign	-0.64	T
MutationAssessor	Benign	-0.90	N
PhyloP100		2.5
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	1.2	N
REVEL	Benign	0.26
Sift	Benign	0.45	T
Sift4G	Benign	0.32	T
Polyphen		0.0010	B
Vest4		0.057
MutPred		0.27		Gain of phosphorylation at P399 (P = 7e-04)
MVP		0.88
ClinPred		0.048	T
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.085
gMVP		0.21
Mutation Taster		=97/3	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: rs797045691; hg19: chrX-153296084;