rs587783104

Positions:

• chrX-154030822-G-C

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP5_Strong BS2 BA1

This summary comes from the ClinGen Evidence Repository: The highest population minor allele frequency of the p.Leu336Val variant in MECP2 (NM_004992.4) in gnomAD v4.1 is 0.001148 in the Middle Eastern population, which is higher than the ClinGen Rett and Angelman-like Disorders VCEP threshold (≥0.0003) for BA1, and therefore meets this criterion (BA1). The p.Leu336Val variant is observed in at least 2 unaffected individuals (internal database - GeneDx) (BS2). The p.Leu336Val variant is found in at least 3 patients with an alternate molecular basis of disease (internal database) (BP5_Strong). In summary, the p.Leu336Val variant in MECP2 is classified as benign based on the ACMG/AMP criteria (BA1, BS2, BP5_Strong). (MECP2 specification v3.0.0; curation approved on 8/30/2024) LINK:https://erepo.genome.network/evrepo/ui/classification/CA294661/MONDO:0010726/036

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0000091 (0 hom. 1 hem.)
• Consequence: MECP2 NM_001110792.2 missense
• Clinical Significance: Benign reviewed by expert panel P:1 U:2 B:1
• Conservation: PhyloP100: 6.72

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 -16 ACMG points.

• BP5: For more information check the summary or visit ClinGen Evidence Repository.
• BS2: For more information check the summary or visit ClinGen Evidence Repository.
• BA1: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MECP2	NM_001110792.2	c.1042C>G	p.Leu348Val	missense_variant	3/3	ENST00000453960.7	NP_001104262.1
MECP2	NM_004992.4	c.1006C>G	p.Leu336Val	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.1042C>G	p.Leu348Val	missense_variant	3/3	1	NM_001110792.2	ENSP00000395535.2
MECP2	ENST00000303391.11	c.1006C>G	p.Leu336Val	missense_variant	4/4	1	NM_004992.4	ENSP00000301948.6

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 0.00000911 AC: 10 AN: 1098252 Hom.: 0 Cov.: 35 AF XY: 0.00000275 AC XY: 1 AN XY: 363606

Gnomad4 AFR exome AF: 0.00

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: 0.00000594

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 23

ClinVar

Significance: Benign

Submissions summary: Pathogenic:1 Uncertain:2 Benign:1

Revision: reviewed by expert panel

Submissions by phenotype

not provided Pathogenic:1 Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Feb 25, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jun 30, 2016	The L336V variant has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. It was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The L336V variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position that is conserved across mammals but not in distantly related species. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant. -
Likely pathogenic, criteria provided, single submitter	research	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	-	- -

Rett syndrome Benign:1

Benign, reviewed by expert panel

curation

ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel

Aug 30, 2024

The highest population minor allele frequency of the p.Leu336Val variant in MECP2 (NM_004992.4) in gnomAD v4.1 is 0.001148 in the Middle Eastern population, which is higher than the ClinGen Rett and Angelman-like Disorders VCEP threshold (≥0.0003) for BA1, and therefore meets this criterion (BA1). The p.Leu336Val variant is observed in at least 2 unaffected individuals (internal database - GeneDx) (BS2). The p.Leu336Val variant is found in at least 3 patients with an alternate molecular basis of disease (internal database) (BP5_Strong). In summary, the p.Leu336Val variant in MECP2 is classified as benign based on the ACMG/AMP criteria (BA1, BS2, BP5_Strong). (MECP2 specification v3.0.0; curation approved on 8/30/2024) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.070
CADD	Benign	21
DANN	Benign	0.23
DEOGEN2	Benign	0.29	T;.
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.90	D;D
M_CAP	Uncertain	0.18	D
MetaRNN	Benign	0.34	T;T
MetaSVM	Uncertain	-0.063	T
MutationAssessor	Benign	0.69	N;.
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-0.14	N;N
REVEL	Uncertain	0.47
Sift	Benign	0.10	T;T
Sift4G	Benign	0.33	T;T
Polyphen		0.60	P;P
Vest4		0.22
MutPred		0.19		Gain of sheet (P = 0.0344);.;
MVP		1.0
ClinPred		0.52	D
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.21
gMVP		0.48

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: rs587783104; hg19: chrX-153296273;