rs63485860

Variant names:

• chrX-154031211-C-G
• rs63485860
• NM_001110792.2:c.653G>C

Your query was ambiguous. Multiple possible variants found:

• chrX-154031211-C-G
• chrX-154031211-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BS1 BP5_Strong BS2

This summary comes from the ClinGen Evidence Repository: The allele frequency of the p.Gly206Ala variant in MECP2 (NM_004992.3) is 0.008% in the European (non-Finnish) sub population in gnomAD, which is high enough to meet the BS1 criteria based on thresholds defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like conditions (BS1). The p.Gly206Ala variant in MECP2 is observed in at least 2 unaffected individuals (PMID 17427193, internal database - GeneDx) (BS2). The p.Gly206Ala variant is found in at least 3 patients with an alternate molecular basis of disease (internal database - GeneDx; internal database - Invitae) (BP5_strong). In summary, the p.Gly206Ala variant in MECP2 is classified as Benign based on the ACMG/AMP criteria (BS1, BS2, BP5_strong). LINK:https://erepo.genome.network/evrepo/ui/classification/CA170346/MONDO:0010726/016

• Frequency:
  • Genomes: 𝑓 0.000081 (0 hom., 3 hem., cov: 23)
  • Exomes 𝑓: 0.000087 (0 hom. 26 hem.)
• Consequence: MECP2 NM_001386137.1 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Benign reviewed by expert panel U:1 B:6
• Conservation: PhyloP100: 3.65

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.

• BP5: For more information check the summary or visit ClinGen Evidence Repository.
• BS1: For more information check the summary or visit ClinGen Evidence Repository.
• BS2: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MECP2	NM_001110792.2	c.653G>C	p.Gly218Ala	missense_variant	Exon 3 of 3	ENST00000453960.7	NP_001104262.1
MECP2	NM_004992.4	c.617G>C	p.Gly206Ala	missense_variant	Exon 4 of 4	ENST00000303391.11	NP_004983.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MECP2	ENST00000453960.7	c.653G>C	p.Gly218Ala	missense_variant	Exon 3 of 3	1	NM_001110792.2	ENSP00000395535.2
MECP2	ENST00000303391.11	c.617G>C	p.Gly206Ala	missense_variant	Exon 4 of 4	1	NM_004992.4	ENSP00000301948.6

Frequencies

GnomAD3 genomes AF: 0.0000811 AC: 9 AN: 110910 Hom.: 0 Cov.: 23 AF XY: 0.0000907 AC XY: 3 AN XY: 33090

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.000171

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000218 AC: 4 AN: 183510 Hom.: 0 AF XY: 0.0000147 AC XY: 1 AN XY: 67940

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000365

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: 0.0000366

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000874 AC: 96 AN: 1098263 Hom.: 0 Cov.: 35 AF XY: 0.0000715 AC XY: 26 AN XY: 363621

Gnomad4 AFR exome AF: 0.00

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: 0.000112

Gnomad4 OTH exome AF: 0.0000217

GnomAD4 genome AF: 0.0000811 AC: 9 AN: 110910 Hom.: 0 Cov.: 23 AF XY: 0.0000907 AC XY: 3 AN XY: 33090

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000171

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000214 Hom.: 1

Bravo AF: 0.0000642

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Benign

Submissions summary: Uncertain:1 Benign:6

Revision: reviewed by expert panel

Submissions by phenotype

Rett syndrome Benign:2

Mar 14, 2024

Centre for Population Genomics, CPG

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: curation

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 allele frequency of this variant in at least one population in gnomAD is between 0.008% and 0.03% (BS1). The variant is observed in at least 2 individuals with no features of Rett Syndrome (BS2). (PMID 1742719, ClinVar Variation ID: 143638) -

Oct 11, 2022

ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel

Significance: Benign

Review Status: reviewed by expert panel

Collection Method: curation

The allele frequency of the p.Gly206Ala variant in MECP2 (NM_004992.3) is 0.008% in the European (non-Finnish) sub population in gnomAD, which is high enough to meet the BS1 criteria based on thresholds defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like conditions (BS1). The p.Gly206Ala variant in MECP2 is observed in at least 2 unaffected individuals (PMID 17427193, internal database - GeneDx) (BS2). The p.Gly206Ala variant is found in at least 3 patients with an alternate molecular basis of disease (internal database - GeneDx; internal database - Invitae) (BP5_strong). In summary, the p.Gly206Ala variant in MECP2 is classified as Benign based on the ACMG/AMP criteria (BS1, BS2, BP5_strong). -

Autism, susceptibility to, X-linked 3 Uncertain:1

Nov 01, 2007

RettBASE

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: curation

- -

not specified Benign:1

May 04, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: MECP2 c.617G>C (p.Gly206Ala) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8.7e-05 in 1209173 control chromosomes. The observed variant frequency is approximately 10.4 fold of the estimated maximal expected allele frequency for a pathogenic variant in MECP2 causing Rett Syndrome phenotype (8.3e-06), strongly suggesting that the variant is benign. c.617G>C has been reported in the literature in at least one individual affected with autism and his asymptomatic mother and maternal grandmother (e.g. Coutinho_2007). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 17427193). ClinVar contains an entry for this variant (Variation ID: 143638). Based on the evidence outlined above, the variant was classified as benign. -

Severe neonatal-onset encephalopathy with microcephaly Benign:1

Apr 05, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

Jan 19, 2018

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 17427193, 26350204) -

MECP2-related disorder Benign:1

Aug 24, 2024

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Pathogenic	0.50	D
BayesDel_noAF	Pathogenic	0.59
CADD	Benign	23
DANN	Benign	0.51
DEOGEN2	Uncertain	0.57	D;.;T;T
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D;D;D;D
M_CAP	Pathogenic	0.77	D
MetaRNN	Uncertain	0.58	D;D;D;D
MetaSVM	Pathogenic	0.81	D
MutationAssessor	Uncertain	2.3	M;.;.;.
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-1.5	N;N;.;.
REVEL	Pathogenic	0.74
Sift	Uncertain	0.0040	D;D;.;.
Sift4G	Benign	0.34	T;T;.;T
Polyphen		1.0	D;D;.;.
Vest4		0.46
MVP		1.0
ClinPred		0.33	T
GERP RS		5.5
Varity_R		0.51
gMVP		0.85

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs63485860; hg19: chrX-153296662;