rs781968415

Variant names:

• chrX-154030726-G-A
• rs781968415
• NM_001110792.2:c.1138C>T

Your query was ambiguous. Multiple possible variants found:

• chrX-154030726-G-A
• chrX-154030726-G-C

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 2P and 6B. PM1 BP4 BP6 BS2

The NM_001110792.2(MECP2):​c.1138C>T​(p.His380Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000348 in 1,207,142 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 9 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H380Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000027 (0 hom., 0 hem., cov: 22)
  • Exomes 𝑓: 0.000036 (0 hom. 9 hem.)
• Consequence: MECP2 NM_001110792.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:1
• Conservation: PhyloP100: 3.28
• Publications: 2 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: Likely_benign. The variant received -4 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 16 benign, 15 uncertain in NM_001110792.2
• BP4: Computational evidence support a benign effect (MetaRNN=0.27562487).
• BP6: Variant X-154030726-G-A is Benign according to our data. Variant chrX-154030726-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 1325581.
• BS2: High AC in GnomAdExome4 at 39 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.1138C>T	p.His380Tyr	missense	Exon 3 of 3	NP_001104262.1
	MECP2	NM_004992.4	MANE Plus Clinical	c.1102C>T	p.His368Tyr	missense	Exon 4 of 4	NP_004983.1
	MECP2	NM_001316337.2		c.823C>T	p.His275Tyr	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.1138C>T	p.His380Tyr	missense	Exon 3 of 3	ENSP00000395535.2
	MECP2	ENST00000303391.11	TSL:1 MANE Plus Clinical	c.1102C>T	p.His368Tyr	missense	Exon 4 of 4	ENSP00000301948.6
	MECP2	ENST00000630151.3	TSL:5	c.1102C>T	p.His368Tyr	missense	Exon 4 of 4	ENSP00000486089.2

Frequencies

GnomAD3 genomes AF: 0.0000271 AC: 3 AN: 110683 Hom.: 0 Cov.: 22

Gnomad AFR AF: 0.0000329

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000190

Gnomad OTH AF: 0.000677

GnomAD2 exomes AF: 0.0000112 AC: 2 AN: 179187 AF XY: 0.00

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000251

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000356 AC: 39 AN: 1096459 Hom.: 0 Cov.: 35 AF XY: 0.0000249 AC XY: 9 AN XY: 362141

African (AFR) AF: 0.00 AC: 0 AN: 26323

American (AMR) AF: 0.00 AC: 0 AN: 35097

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19318

East Asian (EAS) AF: 0.00 AC: 0 AN: 30183

South Asian (SAS) AF: 0.00 AC: 0 AN: 54047

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40220

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4023

European-Non Finnish (NFE) AF: 0.0000440 AC: 37 AN: 841244

Other (OTH) AF: 0.0000435 AC: 2 AN: 46004

GnomAD4 genome AF: 0.0000271 AC: 3 AN: 110683 Hom.: 0 Cov.: 22 AF XY: 0.00 AC XY: 0 AN XY: 32877

African (AFR) AF: 0.0000329 AC: 1 AN: 30374

American (AMR) AF: 0.00 AC: 0 AN: 10493

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2633

East Asian (EAS) AF: 0.00 AC: 0 AN: 3507

South Asian (SAS) AF: 0.00 AC: 0 AN: 2591

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5997

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 239

European-Non Finnish (NFE) AF: 0.0000190 AC: 1 AN: 52689

Other (OTH) AF: 0.000677 AC: 1 AN: 1477

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000151

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Rett syndrome Uncertain:1

Apr 30, 2020

New York Genome Center

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The heterozygous missense variant, p.His380Tyr, identified in MECP2 has not been reported in affected individuals in the literature. The variant has 0.00001 allele frequency in the gnomAD database (3 out of 200,607 heterozygous alleles, no hemizygous males) indicating it is an extremely rare allele. The variant affects an evolutionary conserved residue and is predicted deleterious by multiple in silico prediction tools. However, no functional studies have been performed to evaluate the impact of this variant on normal function of the MECP2 protein. Based on the current evidence, the p.His380Tyr variant in the MECP2 gene is assessed as variant of uncertain significance.

Inborn genetic diseases Uncertain:1

Aug 14, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1102C>T (p.H368Y) alteration is located in exon 4 (coding exon 3) of the MECP2 gene. This alteration results from a C to T substitution at nucleotide position 1102, causing the histidine (H) at amino acid position 368 to be replaced by a tyrosine (Y). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.

MECP2-related disorder Uncertain:1

Jul 05, 2024

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The MECP2 c.1102C>T variant is predicted to result in the amino acid substitution p.His368Tyr. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0055% of alleles in individuals of African descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.

Severe neonatal-onset encephalopathy with microcephaly Benign:1

May 07, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Uncertain	0.043	T
BayesDel_noAF	Benign	-0.12
CADD	Benign	21
DANN	Benign	0.96
DEOGEN2	Benign	0.31	T
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.91	D
M_CAP	Pathogenic	0.31	D
MetaRNN	Benign	0.28	T
MetaSVM	Uncertain	-0.023	T
MutationAssessor	Benign	0.0	N
PhyloP100		3.3
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-0.92	N
REVEL	Uncertain	0.41
Sift	Benign	0.038	D
Sift4G	Benign	0.076	T
Polyphen		0.40	B
Vest4		0.29
MutPred		0.29		Gain of phosphorylation at H368 (P = 0.0026)
MVP		0.97
ClinPred		0.15	T
GERP RS		5.0
Varity_R		0.27
gMVP		0.67
Mutation Taster		=81/19	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: rs781968415; hg19: chrX-153296177;