rs1557134910

Variant names:

• chrX-154030406-A-G
• rs1557134910
• NM_001110792.2:c.1458T>C

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 0P and 3B. BP4 BP5 BS2_Supporting

This summary comes from the ClinGen Evidence Repository: The highest population minor allele frequency of the p.Pro474= variant in MECP2 (NM_004992.3) in gnomAD v4.1 is 0.000008935 in European (Non-Finnish) population (not sufficient to meet BS1 criteria). The p.Pro474= variant is observed in at least 1 unaffected individual (GeneDx internal database) (BS2_supporting). The p.Pro474= variant is found in a patient with an alternate molecular basis of disease (GeneDx internal database) (BP5). Splice prediction analysis does not suggest an impact to splicing (BP4). In summary, the p.Pro474= variant in MECP2 is classified as likely benign based on the ACMG/AMP criteria (BS2_supporting, BP5, BP4). LINK:https://erepo.genome.network/evrepo/ui/classification/CA519704534/MONDO:0010726/036

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 0.0000073 (0 hom. 2 hem.)
• Consequence: MECP2 NM_001110792.2 synonymous
• Clinical Significance: Likely benign reviewed by expert panel U:2 B:3
• Conservation: PhyloP100: 0.536

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 Likely_benign. Variant got -3 ACMG points.

• BP4: For more information check the summary or visit ClinGen Evidence Repository.
• BP5: For more information check the summary or visit ClinGen Evidence Repository.
• BS2: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MECP2	NM_001110792.2	c.1458T>C	p.Pro486Pro	synonymous_variant	Exon 3 of 3	ENST00000453960.7	NP_001104262.1
MECP2	NM_004992.4	c.1422T>C	p.Pro474Pro	synonymous_variant	Exon 4 of 4	ENST00000303391.11	NP_004983.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MECP2	ENST00000453960.7	c.1458T>C	p.Pro486Pro	synonymous_variant	Exon 3 of 3	1	NM_001110792.2	ENSP00000395535.2
MECP2	ENST00000303391.11	c.1422T>C	p.Pro474Pro	synonymous_variant	Exon 4 of 4	1	NM_004992.4	ENSP00000301948.6
MECP2	ENST00000628176	c.*794T>C		3_prime_UTR_variant	Exon 5 of 5	3		ENSP00000486978.1
MECP2	ENST00000407218.5	c.*794T>C		downstream_gene_variant		5		ENSP00000384865.2

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome AF: 0.00000728 AC: 8 AN: 1098213 Hom.: 0 Cov.: 32 AF XY: 0.00000550 AC XY: 2 AN XY: 363567

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000950

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 22

ClinVar

Significance: Likely benign

Submissions summary: Uncertain:2 Benign:3

Revision: reviewed by expert panel

Submissions by phenotype

not provided Uncertain:2

Mar 05, 2018

Athena Diagnostics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 16, 2023

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Rett syndrome Benign:1

Apr 18, 2024

ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel

Significance: Likely benign

Review Status: reviewed by expert panel

Collection Method: curation

The highest population minor allele frequency of the p.Pro474= variant in MECP2 (NM_004992.3) in gnomAD v4.1 is 0.000008935 in European (Non-Finnish) population (not sufficient to meet BS1 criteria). The p.Pro474= variant is observed in at least 1 unaffected individual (GeneDx internal database) (BS2_supporting). The p.Pro474= variant is found in a patient with an alternate molecular basis of disease (GeneDx internal database) (BP5). Splice prediction analysis does not suggest an impact to splicing (BP4). In summary, the p.Pro474= variant in MECP2 is classified as likely benign based on the ACMG/AMP criteria (BS2_supporting, BP5, BP4). -

not specified Benign:1

Jan 29, 2018

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Severe neonatal-onset encephalopathy with microcephaly Benign:1

Apr 16, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.57
CADD	Benign	9.6
DANN	Benign	0.65

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: rs1557134910; hg19: chrX-153295857;