rs61749720

Variant names:

• chrX-154031220-G-A
• rs61749720
• NM_001110792.2:c.644C>T

Your query was ambiguous. Multiple possible variants found:

• chrX-154031220-G-A
• chrX-154031220-G-T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP5 BS2 BA1 BP4

This summary comes from the ClinGen Evidence Repository: The allele frequency of the p.Thr203Met variant in MECP2 is 0.07% in gnomAD, which is high enough to be classified as benign based on thresholds defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like conditions (BA1). The p.Thr203Met variant is observed in at least 2 unaffected individuals (internal database) (BS2). Computational analysis prediction tools suggest that the p.Thr203Met variant does not have a deleterious impact; however this information does not predict clinical significance on its own (BP4). The p.Thr203Met variant is found in a patient with an alternate molecular basis of disease (internal database) (BP5). In summary, the p.Thr203Met variant in MECP2 is classified as benign based on the ACMG/AMP criteria (BA1, BS2, BP4, BP5). LINK:https://erepo.genome.network/evrepo/ui/classification/CA148319/MONDO:0010726/016

• Frequency:
  • Genomes: 𝑓 0.00047 (0 hom., 14 hem., cov: 23)
  • Exomes 𝑓: 0.00044 (0 hom. 156 hem.)
• Consequence: MECP2 NM_001386137.1 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Benign reviewed by expert panel B:10
• Conservation: PhyloP100: 2.57
• Publications: 13 publications found

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]

MECP2 Gene-Disease associations (from GenCC):

• chromosome Xq28 duplication syndrome

  Inheritance: XL Classification: DEFINITIVE Submitted by: G2P
• Rett syndrome

  Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, Ambry Genetics, Orphanet, G2P
• severe neonatal-onset encephalopathy with microcephaly

  Inheritance: XL Classification: DEFINITIVE, SUPPORTIVE Submitted by: G2P, Orphanet
• syndromic X-linked intellectual disability Lubs type

  Inheritance: XL Classification: DEFINITIVE Submitted by: G2P
• atypical Rett syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• non-syndromic X-linked intellectual disability

  Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet
• X-linked intellectual disability-psychosis-macroorchidism syndrome

  Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet
• systemic lupus erythematosus

  Inheritance: Unknown Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: For more information check the summary or visit ClinGen Evidence Repository.
• 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001386137.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MECP2	NM_001110792.2	MANE Select	c.644C>T	p.Thr215Met	missense	Exon 3 of 3	NP_001104262.1	A0A140VKC4
	MECP2	NM_004992.4	MANE Plus Clinical	c.608C>T	p.Thr203Met	missense	Exon 4 of 4	NP_004983.1	D3YJ43
	MECP2	NM_001386137.1		c.-62C>T		5_prime_UTR_premature_start_codon_gain	Exon 6 of 6	NP_001373066.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MECP2	ENST00000453960.7	TSL:1 MANE Select	c.644C>T	p.Thr215Met	missense	Exon 3 of 3	ENSP00000395535.2	P51608-2
	MECP2	ENST00000303391.11	TSL:1 MANE Plus Clinical	c.608C>T	p.Thr203Met	missense	Exon 4 of 4	ENSP00000301948.6	P51608-1
	MECP2	ENST00000630151.3	TSL:5	c.608C>T	p.Thr203Met	missense	Exon 4 of 4	ENSP00000486089.2	P51608-1

Frequencies

GnomAD3 genomes AF: 0.000470 AC: 52 AN: 110637 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.000198

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000759

Gnomad ASJ AF: 0.00114

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00196

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000569

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000747 AC: 137 AN: 183487 AF XY: 0.000604

Gnomad AFR exome AF: 0.000304

Gnomad AMR exome AF: 0.00266

Gnomad ASJ exome AF: 0.000534

Gnomad EAS exome AF: 0.0000721

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000305

Gnomad OTH exome AF: 0.000662

GnomAD4 exome AF: 0.000441 AC: 484 AN: 1098265 Hom.: 0 Cov.: 35 AF XY: 0.000429 AC XY: 156 AN XY: 363619

African (AFR) AF: 0.000303 AC: 8 AN: 26403

American (AMR) AF: 0.00230 AC: 81 AN: 35207

Ashkenazi Jewish (ASJ) AF: 0.000516 AC: 10 AN: 19386

East Asian (EAS) AF: 0.000132 AC: 4 AN: 30206

South Asian (SAS) AF: 0.00115 AC: 62 AN: 54148

European-Finnish (FIN) AF: 0.0000247 AC: 1 AN: 40531

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4137

European-Non Finnish (NFE) AF: 0.000359 AC: 302 AN: 842149

Other (OTH) AF: 0.000347 AC: 16 AN: 46098

GnomAD4 genome AF: 0.000470 AC: 52 AN: 110689 Hom.: 0 Cov.: 23 AF XY: 0.000425 AC XY: 14 AN XY: 32965

African (AFR) AF: 0.000198 AC: 6 AN: 30356

American (AMR) AF: 0.000758 AC: 8 AN: 10558

Ashkenazi Jewish (ASJ) AF: 0.00114 AC: 3 AN: 2634

East Asian (EAS) AF: 0.00 AC: 0 AN: 3512

South Asian (SAS) AF: 0.00196 AC: 5 AN: 2547

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5934

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 218

European-Non Finnish (NFE) AF: 0.000569 AC: 30 AN: 52748

Other (OTH) AF: 0.00 AC: 0 AN: 1497

Alfa AF: 0.000378 Hom.: 18

Bravo AF: 0.000540

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000595 AC: 4

ExAC AF: 0.000618 AC: 75

EpiCase AF: 0.000436

EpiControl AF: 0.000474

ClinVar

ClinVar submissions

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	2	Rett syndrome (2)
-	-	1	Inborn genetic diseases (1)
-	-	1	MECP2-related disorder (1)
-	-	1	not provided (1)
-	-	1	Severe neonatal-onset encephalopathy with microcephaly (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.11
CADD	Benign	15
DANN	Benign	0.95
DEOGEN2	Benign	0.26	T
FATHMM_MKL	Benign	0.58	D
LIST_S2	Benign	0.52	T
M_CAP	Pathogenic	0.48	D
MetaRNN	Benign	0.020	T
MetaSVM	Benign	-0.63	T
PhyloP100		2.6
REVEL	Uncertain	0.30
Sift4G	Uncertain	0.0050	D
Vest4		0.28
MVP		0.74
ClinPred		0.023	T
GERP RS		3.7
Varity_R		0.063
Mutation Taster		=98/2	polymorphism (auto)

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

Other links and lift over

dbSNP: rs61749720; hg19: chrX-153296671;