rs267608339

Positions:

• chrX-154030664-TGGG-T
• chrX-154030664-TGGG-TG
• chrX-154030664-TGGG-TGG
• chrX-154030664-TGGG-TGGGG

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 1P and 12B. PM4_Supporting BP6_Very_Strong BS2

The NM_001110792.2(MECP2):​c.1197_1199del​(p.Pro403del) variant causes a inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000128 in 705,455 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 3 hemizygotes in GnomAD. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. P399P) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.000094 (0 hom., 0 hem., cov: 20)
  • Exomes 𝑓: 0.000010 (0 hom. 3 hem.)
• Consequence: MECP2 NM_001110792.2 inframe_deletion
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2 O:1
• Conservation: PhyloP100: 3.20

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.

• PM4: Nonframeshift variant in NON repetitive region in NM_001110792.2. Strenght limited to Supporting due to length of the change: 1aa.
• BP6: Variant X-154030664-TGGG-T is Benign according to our data. Variant chrX-154030664-TGGG-T is described in ClinVar as [Likely_benign]. Clinvar id is 143389.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-154030664-TGGG-T is described in Lovd as [Benign].
• BS2: High Hemizygotes in GnomAdExome4 at 3 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MECP2	NM_001110792.2	c.1197_1199del	p.Pro403del	inframe_deletion	3/3	ENST00000453960.7
MECP2	NM_004992.4	c.1161_1163del	p.Pro391del	inframe_deletion	4/4	ENST00000303391.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MECP2	ENST00000303391.11	c.1161_1163del	p.Pro391del	inframe_deletion	4/4	1	NM_004992.4	P1
MECP2	ENST00000453960.7	c.1197_1199del	p.Pro403del	inframe_deletion	3/3	1	NM_001110792.2
MECP2	ENST00000407218.5	c.*533_*535del		3_prime_UTR_variant	4/4	5
MECP2	ENST00000628176.2	c.*533_*535del		3_prime_UTR_variant	5/5	3

Frequencies

GnomAD3 genomes AF: 0.0000935 AC: 2 AN: 21381 Hom.: 0 Cov.: 20 AF XY: 0.00 AC XY: 0 AN XY: 5863

Gnomad AFR AF: 0.00

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: 0.000178

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000150 AC: 2 AN: 133195 Hom.: 0 AF XY: 0.0000206 AC XY: 1 AN XY: 48655

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000106

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000154

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000102 AC: 7 AN: 684074 Hom.: 0 AF XY: 0.0000148 AC XY: 3 AN XY: 202488

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000202

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000884

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000935 AC: 2 AN: 21381 Hom.: 0 Cov.: 20 AF XY: 0.00 AC XY: 0 AN XY: 5863

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000178

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000756

ClinVar

Significance: Likely benign

Submissions summary: Benign:2 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

May 15, 2017

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

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Nov 10, 2023

- -

not provided Other:1

not provided, no classification provided

literature only

RettBASE

-

- -

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: rs267608339; hg19: chrX-153296115;