rs143876280

chrX-154030768-G-A

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 2P and 12B. PM1 BP6_Very_Strong BS2

The NM_001110792.2(MECP2):c.1096C>T(p.Arg366Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000827 in 1,209,365 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 35 hemizygotes in GnomAD. Variant has been reported in ClinVar as Benign (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R366L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000054 (0 hom., 2 hem., cov: 23)
  • Exomes 𝑓: 0.000086 (0 hom. 33 hem.)
• Consequence: MECP2 NM_001110792.2 missense
• Clinical Significance: Benign reviewed by expert panel U:3 B:4
• Conservation: PhyloP100: 3.24

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]

ACMG classification

Verdict is Benign. Variant got -10 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 7 benign, 11 uncertain in NM_001110792.2
• BP6: Variant X-154030768-G-A is Benign according to our data. Variant chrX-154030768-G-A is described in ClinVar as [Benign]. Clinvar id is 158880.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chrX-154030768-G-A is described in Lovd as [Likely_benign].
• BS2: High Hemizygotes in GnomAd at 2 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MECP2	NM_001110792.2	c.1096C>T	p.Arg366Cys	missense_variant	3/3	ENST00000453960.7
MECP2	NM_004992.4	c.1060C>T	p.Arg354Cys	missense_variant	4/4	ENST00000303391.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MECP2	ENST00000453960.7	c.1096C>T	p.Arg366Cys	missense_variant	3/3	1	NM_001110792.2
MECP2	ENST00000303391.11	c.1060C>T	p.Arg354Cys	missense_variant	4/4	1	NM_004992.4	P1
MECP2	ENST00000407218.5	c.*432C>T		3_prime_UTR_variant	4/4	5
MECP2	ENST00000628176.2	c.*432C>T		3_prime_UTR_variant	5/5	3

Frequencies

GnomAD3 genomes AF: 0.0000539 AC: 6 AN: 111401 Hom.: 0 Cov.: 23 AF XY: 0.0000595 AC XY: 2 AN XY: 33589

Gnomad AFR AF: 0.0000654

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000282

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000567

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000274 AC: 5 AN: 182156 Hom.: 0 AF XY: 0.0000297 AC XY: 2 AN XY: 67248

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 SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000616

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000856 AC: 94 AN: 1097964 Hom.: 0 Cov.: 35 AF XY: 0.0000908 AC XY: 33 AN XY: 363344

Gnomad4 AFR exome AF: 0.0000379

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000331

Gnomad4 SAS exome AF: 0.0000185

Gnomad4 FIN exome AF: 0.0000247

Gnomad4 NFE exome AF: 0.000102

Gnomad4 OTH exome AF: 0.0000868

GnomAD4 genome AF: 0.0000539 AC: 6 AN: 111401 Hom.: 0 Cov.: 23 AF XY: 0.0000595 AC XY: 2 AN XY: 33589

Gnomad4 AFR AF: 0.0000654

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000282

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000567

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000567

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000297 AC: 2

ExAC AF: 0.0000494 AC: 6

EpiCase AF: 0.000109

EpiControl AF: 0.00

ClinVar

Significance: Benign

Submissions summary: Uncertain:3 Benign:4

Revision: reviewed by expert panel

Submissions by phenotype

not provided Uncertain:2 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 18, 2021	- -
Uncertain significance, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The MECP2 p.R354C variant was not identified in the literature nor was it identified in Cosmic. The variant was identified in dbSNP (ID: rs143876280), LOVD 3.0 and ClinVar (classified as conflicting interpretations of pathogenicity with University of Chicago Genetic Services Laboratory classifying the variant as likely benign and Molecular Diagnostics Lab, Nemours Alfred I. duPont Hospital for Children and EGL Genetics classifying the variant as uncertain significance). The variant was identified in control databases in 5 of 182156 chromosomes (0 homozygous; 2 hemizygous) at a frequency of 0.000027 (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the European (non-Finnish) population in 5 of 81121 chromosomes (freq: 0.00006), but was not observed in the African, Latino, Ashkenazi Jewish, East Asian, European (Finnish), Other or South Asian populations. The p.Arg354 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 03, 2015	- -

not specified Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Dec 20, 2013	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Molecular Diagnostics Lab, Nemours Children's Health, Delaware	Jul 06, 2015	- -

Rett syndrome Benign:1

Benign, reviewed by expert panel

curation

ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel

Dec 09, 2022

The allele frequency of the p.Arg354Cys variant in MECP2 (NM_004992.3) is 0.028% in East Asian 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.Arg354Cys variant is observed in at least 2 unaffected individuals (internal database) (BS2). In summary, the p.Arg354Cys variant in MECP2 is classified as Benign based on the ACMG/AMP criteria (BS1, BS2). -

Severe neonatal-onset encephalopathy with microcephaly Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Oct 23, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.29
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Pathogenic	0.17
Cadd	Uncertain	23
Dann	Uncertain	0.99
DEOGEN2	Benign	0.29	T;.
FATHMM_MKL	Benign	0.74	D
LIST_S2	Uncertain	0.95	D;D
M_CAP	Pathogenic	0.66	D
MetaRNN	Uncertain	0.45	T;T
MetaSVM	Uncertain	0.21	D
MutationAssessor	Benign	1.4	L;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-0.27	N;N
REVEL	Uncertain	0.54
Sift	Uncertain	0.0010	D;D
Sift4G	Uncertain	0.053	T;T
Polyphen		0.97	D;D
Vest4		0.42
MVP		0.95
ClinPred		0.27	T
GERP RS		5.1
Varity_R		0.18
gMVP		0.70

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

Publications

LitVar

Other links and lift over

dbSNP: rs143876280; hg19: chrX-153296219; COSMIC: COSV57655415; COSMIC: COSV57655415;