X-154031195-C-G

Variant names:

• chrX-154031195-C-G
• rs61749731
• NM_001110792.2:c.669G>C

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BS1 BS2

The NM_001110792.2(MECP2):​c.669G>C​(p.Arg223Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000105 in 1,208,524 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 29 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar. Synonymous variant affecting the same amino acid position (i.e. R223R) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00014 (0 hom., 3 hem., cov: 23)
  • Exomes 𝑓: 0.00010 (0 hom. 26 hem.)
• Consequence: MECP2 NM_001110792.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.628
• Publications: 0 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: Benign. The variant received -18 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.16021931).
• BP6: Variant X-154031195-C-G is Benign according to our data. Variant chrX-154031195-C-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 143644.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population amr. GnomAdExome4 allele frequency = 0.000102 (112/1098264) while in subpopulation AMR AF = 0.000767 (27/35206). AF 95% confidence interval is 0.00054. There are 0 homozygotes in GnomAdExome4. There are 26 alleles in the male GnomAdExome4 subpopulation. Median coverage is 35. This position passed quality control check.
• BS2: High AC in GnomAd4 at 15 XL,Unknown,AD gene.

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.669G>C	p.Arg223Ser	missense	Exon 3 of 3	NP_001104262.1
	MECP2	NM_004992.4	MANE Plus Clinical	c.633G>C	p.Arg211Ser	missense	Exon 4 of 4	NP_004983.1
	MECP2	NM_001316337.2		c.354G>C	p.Arg118Ser	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.669G>C	p.Arg223Ser	missense	Exon 3 of 3	ENSP00000395535.2
	MECP2	ENST00000303391.11	TSL:1 MANE Plus Clinical	c.633G>C	p.Arg211Ser	missense	Exon 4 of 4	ENSP00000301948.6
	MECP2	ENST00000630151.3	TSL:5	c.633G>C	p.Arg211Ser	missense	Exon 4 of 4	ENSP00000486089.2

Frequencies

GnomAD3 genomes AF: 0.000136 AC: 15 AN: 110210 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.000166

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000667

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: 0.0000381

Gnomad OTH AF: 0.000681

GnomAD2 exomes AF: 0.000196 AC: 36 AN: 183523 AF XY: 0.000147

Gnomad AFR exome AF: 0.000152

Gnomad AMR exome AF: 0.000875

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000721

Gnomad FIN exome AF: 0.0000625

Gnomad NFE exome AF: 0.0000732

Gnomad OTH exome AF: 0.000441

GnomAD4 exome AF: 0.000102 AC: 112 AN: 1098264 Hom.: 0 Cov.: 35 AF XY: 0.0000715 AC XY: 26 AN XY: 363618

African (AFR) AF: 0.000151 AC: 4 AN: 26403

American (AMR) AF: 0.000767 AC: 27 AN: 35206

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19386

East Asian (EAS) AF: 0.0000331 AC: 1 AN: 30206

South Asian (SAS) AF: 0.00 AC: 0 AN: 54149

European-Finnish (FIN) AF: 0.0000247 AC: 1 AN: 40531

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4137

European-Non Finnish (NFE) AF: 0.0000902 AC: 76 AN: 842148

Other (OTH) AF: 0.0000651 AC: 3 AN: 46098

GnomAD4 genome AF: 0.000136 AC: 15 AN: 110260 Hom.: 0 Cov.: 23 AF XY: 0.0000923 AC XY: 3 AN XY: 32510

African (AFR) AF: 0.000165 AC: 5 AN: 30251

American (AMR) AF: 0.000666 AC: 7 AN: 10511

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2623

East Asian (EAS) AF: 0.00 AC: 0 AN: 3486

South Asian (SAS) AF: 0.00 AC: 0 AN: 2452

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6021

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 214

European-Non Finnish (NFE) AF: 0.0000381 AC: 2 AN: 52537

Other (OTH) AF: 0.000672 AC: 1 AN: 1488

Alfa AF: 0.000130 Hom.: 1

Bravo AF: 0.000193

ExAC AF: 0.0000824 AC: 10

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	2	not specified (2)
-	-	1	Inborn genetic diseases (1)
-	-	1	MECP2-related disorder (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	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Pathogenic	0.39
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.55	D
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Pathogenic	0.89	D
MetaRNN	Benign	0.16	T
MetaSVM	Uncertain	0.46	D
MutationAssessor	Uncertain	2.2	M
PhyloP100		0.63
PrimateAI	Uncertain	0.75	T
PROVEAN	Benign	-0.49	N
REVEL	Uncertain	0.54
Sift	Uncertain	0.0030	D
Sift4G	Benign	0.11	T
Polyphen		0.90	P
Vest4		0.56
MutPred		0.37		Gain of ubiquitination at K210 (P = 0.0199)
MVP		0.99
ClinPred		0.056	T
GERP RS		5.5
Varity_R		0.62
gMVP		0.92
Mutation Taster		=31/69	disease causing

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: rs61749731; hg19: chrX-153296646;