rs267608502

Positions:

• chrX-154031232-G-A
• chrX-154031232-G-C
• chrX-154031232-G-T

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4 BP6_Moderate BS2

The NM_001110792.2(MECP2):​c.632C>T​(p.Pro211Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00001 in 1,098,263 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. Variant has been reported in ClinVar as Likely benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P211S) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.000010 (0 hom. 3 hem.)
• Consequence: MECP2 NM_001110792.2 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 3.27

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 -7 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.32124346).
• BP6: Variant X-154031232-G-A is Benign according to our data. Variant chrX-154031232-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 940151.Status of the report is criteria_provided_single_submitter, 1 stars.
• 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.632C>T	p.Pro211Leu	missense_variant	3/3	ENST00000453960.7
MECP2	NM_004992.4	c.596C>T	p.Pro199Leu	missense_variant	4/4	ENST00000303391.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MECP2	ENST00000453960.7	c.632C>T	p.Pro211Leu	missense_variant	3/3	1	NM_001110792.2
MECP2	ENST00000303391.11	c.596C>T	p.Pro199Leu	missense_variant	4/4	1	NM_004992.4	P1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD3 exomes AF: 0.00000545 AC: 1 AN: 183431 Hom.: 0 AF XY: 0.0000147 AC XY: 1 AN XY: 67883

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000122

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000100 AC: 11 AN: 1098263 Hom.: 0 Cov.: 34 AF XY: 0.00000825 AC XY: 3 AN XY: 363617

Gnomad4 AFR exome AF: 0.0000379

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000107

Gnomad4 OTH exome AF: 0.0000217

GnomAD4 genome Cov.: 23

Bravo AF: 0.00000378

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Severe neonatal-onset encephalopathy with microcephaly Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Sep 12, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Uncertain	-0.010
CADD	Uncertain	23
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.46	T;.;T;T
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Uncertain	0.96	D;D;D;D
M_CAP	Pathogenic	0.71	D
MetaRNN	Benign	0.32	T;T;T;T
MetaSVM	Uncertain	0.79	D
MutationAssessor	Benign	1.5	L;.;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-1.1	N;N;.;.
REVEL	Uncertain	0.40
Sift	Uncertain	0.0040	D;D;.;.
Sift4G	Uncertain	0.044	D;T;.;T
Polyphen		0.010	B;B;.;.
Vest4		0.16
MutPred		0.13		Loss of glycosylation at P199 (P = 0.0216);.;Loss of glycosylation at P199 (P = 0.0216);.;
MVP		0.99
ClinPred		0.27	T
GERP RS		5.5
Varity_R		0.22
gMVP		0.37

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: rs267608502; hg19: chrX-153296683;