rs1557135898

Positions:

• chrX-154030730-G-A

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 2P and 13B. PM2 BP4_Strong BP6_Very_Strong BP7

The NM_001110792.2(MECP2):​c.1134C>T​(p.His378=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000182 in 1,096,702 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0000018 (0 hom. 1 hem.)
• Consequence: MECP2 NM_001110792.2 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.33

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 -11 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.57).
• BP6: Variant X-154030730-G-A is Benign according to our data. Variant chrX-154030730-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 548124.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.33 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MECP2	NM_001110792.2	c.1134C>T	p.His378=	synonymous_variant	3/3	ENST00000453960.7
MECP2	NM_004992.4	c.1098C>T	p.His366=	synonymous_variant	4/4	ENST00000303391.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MECP2	ENST00000453960.7	c.1134C>T	p.His378=	synonymous_variant	3/3	1	NM_001110792.2
MECP2	ENST00000303391.11	c.1098C>T	p.His366=	synonymous_variant	4/4	1	NM_004992.4	P1
MECP2	ENST00000407218.5	c.*470C>T		3_prime_UTR_variant	4/4	5
MECP2	ENST00000628176.2	c.*470C>T		3_prime_UTR_variant	5/5	3

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 0.00000182 AC: 2 AN: 1096702 Hom.: 0 Cov.: 35 AF XY: 0.00000276 AC XY: 1 AN XY: 362352

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000185

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000217

GnomAD4 genome Cov.: 23

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Rett syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital

Jun 14, 2018

- -

Severe neonatal-onset encephalopathy with microcephaly Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 03, 2024

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Oct 12, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.57
CADD	Benign	2.6
DANN	Benign	0.60

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: rs1557135898; hg19: chrX-153296181;