X-154030639-C-T

Variant names:

• chrX-154030639-C-T
• rs56268439
• NM_001110792.2:c.1225G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BS2 BA1

This summary comes from the ClinGen Evidence Repository: The allele frequency of the p.Glu397Lys variant in MECP2 (NM_004992) is 0.393% in European (Non-Finnish) sub population in gnomAD, which is high enough to be classified as Benign based on thresholds defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like conditions (BA1). The p.Glu397Lys variant is observed in at least 2 unaffected individuals (PMID 10577905,12384770, RettBASE) (BS2). In summary, the p.Glu397Lys variant in MECP2 is classified as Benign based on the ACMG/AMP criteria applied (BA1, BS2). LINK:https://erepo.genome.network/evrepo/ui/classification/CA211306/MONDO:0010726/016

• Frequency:
  • Genomes: 𝑓 0.0031 (0 hom., 44 hem., cov: 18)
  • Exomes 𝑓: 0.0049 (11 hom. 1499 hem.)
• Consequence: MECP2 NM_001110792.2 missense
• Clinical Significance: Benign reviewed by expert panel U:1 B:20
• Conservation: PhyloP100: 0.579
• Publications: 19 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: Benign. The variant received -12 ACMG points.

• BS2: For more information check the summary or visit ClinGen Evidence Repository.
• BA1: 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.1225G>A	p.Glu409Lys	missense	Exon 3 of 3	NP_001104262.1	A0A140VKC4
	MECP2	NM_004992.4	MANE Plus Clinical	c.1189G>A	p.Glu397Lys	missense	Exon 4 of 4	NP_004983.1	D3YJ43
	MECP2	NM_001316337.2		c.910G>A	p.Glu304Lys	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.1225G>A	p.Glu409Lys	missense	Exon 3 of 3	ENSP00000395535.2	P51608-2
	MECP2	ENST00000303391.11	TSL:1 MANE Plus Clinical	c.1189G>A	p.Glu397Lys	missense	Exon 4 of 4	ENSP00000301948.6	P51608-1
	MECP2	ENST00000630151.3	TSL:5	c.1189G>A	p.Glu397Lys	missense	Exon 4 of 4	ENSP00000486089.2	P51608-1

Frequencies

GnomAD3 genomes AF: 0.00313 AC: 258 AN: 82421 Hom.: 0 Cov.: 18

Gnomad AFR AF: 0.00121

Gnomad AMI AF: 0.00176

Gnomad AMR AF: 0.00195

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000678

Gnomad FIN AF: 0.00254

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00472

Gnomad OTH AF: 0.00289

GnomAD2 exomes AF: 0.00223 AC: 388 AN: 173875 AF XY: 0.00253

Gnomad AFR exome AF: 0.00119

Gnomad AMR exome AF: 0.000809

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000731

Gnomad FIN exome AF: 0.00140

Gnomad NFE exome AF: 0.00394

Gnomad OTH exome AF: 0.00342

GnomAD4 exome AF: 0.00485 AC: 4761 AN: 981331 Hom.: 11 Cov.: 33 AF XY: 0.00481 AC XY: 1499 AN XY: 311627

African (AFR) AF: 0.00171 AC: 40 AN: 23364

American (AMR) AF: 0.000822 AC: 27 AN: 32842

Ashkenazi Jewish (ASJ) AF: 0.0000639 AC: 1 AN: 15646

East Asian (EAS) AF: 0.0000846 AC: 2 AN: 23628

South Asian (SAS) AF: 0.000779 AC: 38 AN: 48781

European-Finnish (FIN) AF: 0.00254 AC: 67 AN: 26401

Middle Eastern (MID) AF: 0.00124 AC: 4 AN: 3217

European-Non Finnish (NFE) AF: 0.00574 AC: 4409 AN: 768697

Other (OTH) AF: 0.00446 AC: 173 AN: 38755

GnomAD4 genome AF: 0.00313 AC: 258 AN: 82427 Hom.: 0 Cov.: 18 AF XY: 0.00229 AC XY: 44 AN XY: 19179

African (AFR) AF: 0.00121 AC: 25 AN: 20710

American (AMR) AF: 0.00195 AC: 13 AN: 6675

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2252

East Asian (EAS) AF: 0.00 AC: 0 AN: 2562

South Asian (SAS) AF: 0.000681 AC: 1 AN: 1468

European-Finnish (FIN) AF: 0.00254 AC: 8 AN: 3145

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 169

European-Non Finnish (NFE) AF: 0.00472 AC: 207 AN: 43827

Other (OTH) AF: 0.00286 AC: 3 AN: 1050

Alfa AF: 0.00229 Hom.: 25

Bravo AF: 0.00288

TwinsUK AF: 0.00243 AC: 9

ALSPAC AF: 0.00242 AC: 7

ESP6500AA AF: 0.00183 AC: 7

ESP6500EA AF: 0.00359 AC: 24

ExAC AF: 0.00251 AC: 304

ClinVar

ClinVar submissions

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	10	not specified (10)
-	-	4	not provided (4)
-	1	3	Rett syndrome (4)
-	-	1	History of neurodevelopmental disorder (1)
-	-	1	Rett syndrome;C0796222:X-linked intellectual disability-psychosis-macroorchidism syndrome;C1845336:Autism, susceptibility to, X-linked 3;C1846058:Syndromic X-linked intellectual disability Lubs type;C1968556:Severe neonatal-onset encephalopathy with microcephaly (1)
-	-	1	Severe neonatal-onset encephalopathy with microcephaly (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.058
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	14
DANN	Benign	0.50
DEOGEN2	Benign	0.23	T
FATHMM_MKL	Benign	0.46	N
LIST_S2	Uncertain	0.86	D
M_CAP	Pathogenic	0.49	D
MetaRNN	Benign	0.010	T
MetaSVM	Benign	-0.83	T
MutationAssessor	Benign	-0.81	N
PhyloP100		0.58
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	0.020	N
REVEL	Uncertain	0.40
Sift	Benign	0.44	T
Sift4G	Benign	0.99	T
Polyphen		0.0	B
Vest4		0.32
MVP		0.74
ClinPred		0.0080	T
GERP RS		3.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.055
gMVP		0.24
Mutation Taster		=92/8	polymorphism (auto)

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: rs56268439; hg19: chrX-153296090; COSMIC: COSV100317790; COSMIC: COSV100317790;