rs376821032

chrX-154031333-G-AchrX-154031333-G-C

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_Moderate BP6_Very_Strong BP7 BS2

The NM_001110792.2(MECP2):c.531C>T(p.Pro177=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000132 in 1,210,371 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 7 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. P177P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000027 (0 hom., 2 hem., cov: 22)
  • Exomes 𝑓: 0.000012 (0 hom. 5 hem.)
• Consequence: MECP2 NM_001110792.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.472

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 -15 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.22745731).
• BP6: Variant X-154031333-G-A is Benign according to our data. Variant chrX-154031333-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 536590.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.472 with no splicing effect.
• BS2: High Hemizygotes in GnomAd at 2 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MECP2	NM_001110792.2	c.531C>T	p.Pro177=	synonymous_variant	3/3	ENST00000453960.7
MECP2	NM_004992.4	c.495C>T	p.Pro165=	synonymous_variant	4/4	ENST00000303391.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MECP2	ENST00000453960.7	c.531C>T	p.Pro177=	synonymous_variant	3/3	1	NM_001110792.2
MECP2	ENST00000303391.11	c.495C>T	p.Pro165=	synonymous_variant	4/4	1	NM_004992.4	P1

Frequencies

GnomAD3 genomes AF: 0.0000268 AC: 3 AN: 112124 Hom.: 0 Cov.: 22 AF XY: 0.0000584 AC XY: 2 AN XY: 34264

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000939

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: 0.0000376

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000164 AC: 3 AN: 182979 Hom.: 0 AF XY: 0.0000148 AC XY: 1 AN XY: 67557

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: 0.0000368

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000118 AC: 13 AN: 1098247 Hom.: 0 Cov.: 34 AF XY: 0.0000138 AC XY: 5 AN XY: 363601

Gnomad4 AFR exome AF: 0.0000379

Gnomad4 AMR exome AF: 0.0000284

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: 0.0000131

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000268 AC: 3 AN: 112124 Hom.: 0 Cov.: 22 AF XY: 0.0000584 AC XY: 2 AN XY: 34264

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000939

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000376

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000214 Hom.: 1

Bravo AF: 0.0000264

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000149 AC: 1

ExAC AF: 0.0000412 AC: 5

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

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

Invitae

Dec 18, 2023

- -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 15, 2017

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.54
Cadd	Benign	9.4
Dann	Benign	0.79
DEOGEN2	Benign	0.084	T
FATHMM_MKL	Benign	0.74	D
LIST_S2	Benign	0.26	T
MetaRNN	Benign	0.23	T
MutationTaster	Benign	1.0	D;D;D
Vest4		0.39
MVP		0.97
GERP RS		2.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs376821032; hg19: chrX-153296784;