rs191076920

chrX-154031511-G-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_001110792.2(MECP2):c.414-61C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000506 in 1,166,546 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 187 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.00054 (0 hom., 18 hem., cov: 23)
  • Exomes 𝑓: 0.00050 (0 hom. 169 hem.)
• Consequence: MECP2 NM_001110792.2 intron
• Clinical Significance: Benign criteria provided, single submitter U:1 B:1 O:1
• Conservation: PhyloP100: 0.445

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant X-154031511-G-C is Benign according to our data. Variant chrX-154031511-G-C is described in ClinVar as [Benign]. Clinvar id is 156070.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000544 (61/112107) while in subpopulation NFE AF= 0.000997 (53/53165). AF 95% confidence interval is 0.000782. There are 0 homozygotes in gnomad4. There are 18 alleles in male gnomad4 subpopulation. Median coverage is 23. This position pass quality control queck.
• BS2: High Hemizygotes in GnomAd at 18 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MECP2	NM_001110792.2	c.414-61C>G		intron_variant		ENST00000453960.7
MECP2	NM_004992.4	c.378-61C>G		intron_variant		ENST00000303391.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MECP2	ENST00000303391.11	c.378-61C>G		intron_variant		1	NM_004992.4	P1
MECP2	ENST00000453960.7	c.414-61C>G		intron_variant		1	NM_001110792.2

Frequencies

GnomAD3 genomes AF: 0.000553 AC: 62 AN: 112054 Hom.: 0 Cov.: 23 AF XY: 0.000526 AC XY: 18 AN XY: 34192

Gnomad AFR AF: 0.0000325

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000283

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000163

Gnomad MID AF: 0.00418

Gnomad NFE AF: 0.000997

Gnomad OTH AF: 0.00199

GnomAD4 exome AF: 0.000502 AC: 529 AN: 1054439 Hom.: 0 AF XY: 0.000519 AC XY: 169 AN XY: 325411

Gnomad4 AFR exome AF: 0.0000391

Gnomad4 AMR exome AF: 0.000199

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000333

Gnomad4 SAS exome AF: 0.000698

Gnomad4 FIN exome AF: 0.000102

Gnomad4 NFE exome AF: 0.000577

Gnomad4 OTH exome AF: 0.000224

GnomAD4 genome AF: 0.000544 AC: 61 AN: 112107 Hom.: 0 Cov.: 23 AF XY: 0.000525 AC XY: 18 AN XY: 34255

Gnomad4 AFR AF: 0.0000324

Gnomad4 AMR AF: 0.000282

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000163

Gnomad4 NFE AF: 0.000997

Gnomad4 OTH AF: 0.00197

Alfa AF: 0.00103 Hom.: 5

Bravo AF: 0.000416

ClinVar

Significance: Benign

Submissions summary: Uncertain:1 Benign:1 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

X-linked intellectual disability-psychosis-macroorchidism syndrome Uncertain:1

Uncertain significance, no assertion criteria provided

curation

RettBASE

Feb 15, 2002

- -

Rett syndrome Benign:1

Benign, criteria provided, single submitter

curation

Centre for Population Genomics, CPG

Mar 18, 2024

This variant has been collected from RettBASE and curated to current modified ACMG/AMP criteria. Based on the classification scheme defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like Disorders Specifications to the ACMG/AMP Variant Interpretation Guidelines VCEP 3.0, this variant is classified as benign. At least the following criteria are met: The allele frequency of this variant in at least one population in gnomAD is higher than the 0.03% threshold defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like Disorders VCEP 3.0 (BA1). -

not provided Other:1

not provided, flagged submission

literature only

RettBASE

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
Cadd	Benign	10
Dann	Benign	0.60
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs191076920; hg19: chrX-153296962;