rs267608344

Positions:

• chrX-154030312-G-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Moderate BP6_Moderate BS1 BS2

The NM_001110792.2(MECP2):​c.*55C>G variant causes a 3 prime UTR change. The variant allele was found at a frequency of 0.000124 in 1,205,688 control chromosomes in the GnomAD database, including 3 homozygotes. There are 36 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.00013 (1 hom., 1 hem., cov: 22)
  • Exomes 𝑓: 0.00012 (2 hom. 35 hem.)
• Consequence: MECP2 NM_001110792.2 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:2
• Conservation: PhyloP100: 4.29

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.45).
• BP6: Variant X-154030312-G-C is Benign according to our data. Variant chrX-154030312-G-C is described in ClinVar as [Benign]. Clinvar id is 143279.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-154030312-G-C is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000135 (15/111292) while in subpopulation EAS AF= 0.0014 (5/3565). AF 95% confidence interval is 0.000552. There are 1 homozygotes in gnomad4. There are 1 alleles in male gnomad4 subpopulation. Median coverage is 22. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 2 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MECP2	NM_001110792.2	c.*55C>G		3_prime_UTR_variant	3/3	ENST00000453960.7	NP_001104262.1
MECP2	NM_004992.4	c.*55C>G		3_prime_UTR_variant	4/4	ENST00000303391.11	NP_004983.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MECP2	ENST00000453960	c.*55C>G		3_prime_UTR_variant	3/3	1	NM_001110792.2	ENSP00000395535.2
MECP2	ENST00000303391	c.*55C>G		3_prime_UTR_variant	4/4	1	NM_004992.4	ENSP00000301948.6
MECP2	ENST00000628176	c.*888C>G		3_prime_UTR_variant	5/5	3		ENSP00000486978.1

Frequencies

GnomAD3 genomes AF: 0.000135 AC: 15 AN: 111292 Hom.: 1 Cov.: 22 AF XY: 0.0000299 AC XY: 1 AN XY: 33480

Gnomad AFR AF: 0.0000327

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000759

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00140

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000671

GnomAD3 exomes AF: 0.0000765 AC: 14 AN: 183065 Hom.: 1 AF XY: 0.0000296 AC XY: 2 AN XY: 67585

Gnomad AFR exome AF: 0.0000762

Gnomad AMR exome AF: 0.0000365

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000866

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000122 AC: 134 AN: 1094396 Hom.: 2 Cov.: 30 AF XY: 0.0000972 AC XY: 35 AN XY: 359936

Gnomad4 AFR exome AF: 0.0000380

Gnomad4 AMR exome AF: 0.0000284

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000662

Gnomad4 SAS exome AF: 0.0000370

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000119

Gnomad4 OTH exome AF: 0.00237

GnomAD4 genome AF: 0.000135 AC: 15 AN: 111292 Hom.: 1 Cov.: 22 AF XY: 0.0000299 AC XY: 1 AN XY: 33480

Gnomad4 AFR AF: 0.0000327

Gnomad4 AMR AF: 0.000759

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00140

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.000671

Alfa AF: 0.000304 Hom.: 1

Bravo AF: 0.000140

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Benign, no assertion criteria provided

curation

RettBASE

Aug 24, 2010

- -

Rett syndrome Benign:1

Benign, criteria provided, single submitter

curation

Centre for Population Genomics, CPG

Oct 04, 2023

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 2.0, 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 2.0 (BA1). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.45
CADD	Benign	17
DANN	Benign	0.88

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: rs267608344; hg19: chrX-153295763;