X-154097618-GCCT-G

Position:

• chrX-154097618-GCCT-G

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The ENST00000453960.7(MECP2):​c.45_47del​(p.Gly16del) variant causes a inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000404 in 1,019,857 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 6 hemizygotes in GnomAD. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. G15G) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000048 (0 hom., 1 hem., cov: 20)
  • Exomes 𝑓: 0.00044 (0 hom. 5 hem.)
• Consequence: MECP2 ENST00000453960.7 inframe_deletion
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 3.07

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 -16 ACMG points.

• BP6: Variant X-154097618-GCCT-G is Benign according to our data. Variant chrX-154097618-GCCT-G is described in ClinVar as [Likely_benign]. Clinvar id is 517006.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-154097618-GCCT-G is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population amr. gnomad4_exome allele frequency = 0.000444 (407/915645) while in subpopulation AMR AF= 0.00166 (33/19891). AF 95% confidence interval is 0.00121. There are 0 homozygotes in gnomad4_exome. There are 5 alleles in male gnomad4_exome subpopulation. This position pass quality control queck.
• BS2: High Hemizygotes in GnomAdExome4 at 5 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MECP2	NM_001110792.2	c.45_47del	p.Gly16del	inframe_deletion	1/3	ENST00000453960.7	NP_001104262.1
MECP2	NM_004992.4	c.-116_-114del		5_prime_UTR_variant	1/4	ENST00000303391.11	NP_004983.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MECP2	ENST00000453960.7	c.45_47del	p.Gly16del	inframe_deletion	1/3	1	NM_001110792.2	ENSP00000395535
MECP2	ENST00000303391.11	c.-116_-114del		5_prime_UTR_variant	1/4	1	NM_004992.4	ENSP00000301948	P1

Frequencies

GnomAD3 genomes AF: 0.0000480 AC: 5 AN: 104172 Hom.: 0 Cov.: 20 AF XY: 0.0000347 AC XY: 1 AN XY: 28794

Gnomad AFR AF: 0.0000345

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000988

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000639

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000199

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.000444 AC: 407 AN: 915645 Hom.: 0 AF XY: 0.0000179 AC XY: 5 AN XY: 279779

Gnomad4 AFR exome AF: 0.000551

Gnomad4 AMR exome AF: 0.00166

Gnomad4 ASJ exome AF: 0.00132

Gnomad4 EAS exome AF: 0.000467

Gnomad4 SAS exome AF: 0.00102

Gnomad4 FIN exome AF: 0.00132

Gnomad4 NFE exome AF: 0.000335

Gnomad4 OTH exome AF: 0.000601

GnomAD4 genome AF: 0.0000480 AC: 5 AN: 104212 Hom.: 0 Cov.: 20 AF XY: 0.0000347 AC XY: 1 AN XY: 28838

Gnomad4 AFR AF: 0.0000344

Gnomad4 AMR AF: 0.0000987

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000642

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000199

Gnomad4 OTH AF: 0.00

Alfa AF: 0.00267 Hom.: 6

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Severe neonatal-onset encephalopathy with microcephaly Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 14, 2023

- -

Inborn genetic diseases Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 31, 2019

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Oct 19, 2020

- -

MECP2-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 17, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

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: rs587783744; hg19: chrX-153363075;