rs267608622

Positions:

• chrX-154030540-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Moderate BP6_Very_Strong BS2

The NM_001110792.2(MECP2):​c.1324C>T​(p.Pro442Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000109 in 1,097,836 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 3 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 11/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 0.000011 (0 hom. 3 hem.)
• Consequence: MECP2 NM_001110792.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.50

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 (MetaRNN=0.21211839).
• BP6: Variant X-154030540-G-A is Benign according to our data. Variant chrX-154030540-G-A is described in ClinVar as [Benign]. Clinvar id is 143456.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-154030540-G-A 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	Protein	UniProt
MECP2	NM_001110792.2	c.1324C>T	p.Pro442Ser	missense_variant	3/3	ENST00000453960.7	NP_001104262.1
MECP2	NM_004992.4	c.1288C>T	p.Pro430Ser	missense_variant	4/4	ENST00000303391.11	NP_004983.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MECP2	ENST00000453960.7	c.1324C>T	p.Pro442Ser	missense_variant	3/3	1	NM_001110792.2	ENSP00000395535.2
MECP2	ENST00000303391.11	c.1288C>T	p.Pro430Ser	missense_variant	4/4	1	NM_004992.4	ENSP00000301948.6
MECP2	ENST00000628176	c.*660C>T		3_prime_UTR_variant	5/5	3		ENSP00000486978.1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD3 exomes AF: 0.0000164 AC: 3 AN: 182893 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 67407

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000722

Gnomad SAS exome AF: 0.0000524

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000122

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000109 AC: 12 AN: 1097836 Hom.: 0 Cov.: 32 AF XY: 0.00000826 AC XY: 3 AN XY: 363240

Gnomad4 AFR exome AF: 0.0000758

Gnomad4 AMR exome AF: 0.0000284

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000185

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000831

Gnomad4 OTH exome AF: 0.0000217

GnomAD4 genome Cov.: 22

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Benign

Submissions summary: Benign:3

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

Sep 08, 2023

- -

not specified Benign:1

Benign, no assertion criteria provided

curation

RettBASE

Mar 29, 2011

- -

Rett syndrome Benign:1

Benign, criteria provided, single submitter

curation

Centre for Population Genomics, CPG

Mar 13, 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 variant is observed in at least 2 individuals with no features of Rett Syndrome (BS2).PMID: 21285040 The allele frequency of this variant in at least one population in gnomAD is between 0.008% and 0.03% (BS1). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.094
BayesDel_addAF	Uncertain	0.022	T
BayesDel_noAF	Uncertain	-0.020
CADD	Benign	18
DANN	Benign	0.96
DEOGEN2	Benign	0.25	T;.
FATHMM_MKL	Benign	0.74	D
LIST_S2	Benign	0.70	T;T
M_CAP	Uncertain	0.16	D
MetaRNN	Benign	0.21	T;T
MetaSVM	Benign	-0.59	T
MutationAssessor	Benign	0.34	N;.
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-0.12	N;N
REVEL	Uncertain	0.49
Sift	Uncertain	0.012	D;D
Sift4G	Benign	0.082	T;T
Polyphen		0.0080	B;B
Vest4		0.34
MutPred		0.14		Gain of phosphorylation at P430 (P = 0.0328);.;
MVP		0.98
ClinPred		0.056	T
GERP RS		3.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.072
gMVP		0.23

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: rs267608622; hg19: chrX-153295991;