rs61749739

Variant names:

• chrX-154031142-G-A
• rs61749739
• NM_001110792.2:c.722C>T

Your query was ambiguous. Multiple possible variants found:

• chrX-154031142-G-A
• chrX-154031142-G-T

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 2P and 13B. PM1 BP4 BP6_Very_Strong BS2

The NM_001110792.2(MECP2):​c.722C>T​(p.Ser241Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000329 in 1,208,086 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 123 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. S241S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00017 (0 hom., 8 hem., cov: 23)
  • Exomes 𝑓: 0.00034 (0 hom. 115 hem.)
• Consequence: MECP2 NM_001110792.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 4.35
• Publications: 11 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: Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics, ClinGen, 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 -11 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 7 benign, 13 uncertain in NM_001110792.2
• BP4: Computational evidence support a benign effect (MetaRNN=0.36688653).
• BP6: Variant X-154031142-G-A is Benign according to our data. Variant chrX-154031142-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 143659.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 19 XL,Unknown,AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001110792.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MECP2	NM_001110792.2	MANE Select	c.722C>T	p.Ser241Leu	missense	Exon 3 of 3	NP_001104262.1
	MECP2	NM_004992.4	MANE Plus Clinical	c.686C>T	p.Ser229Leu	missense	Exon 4 of 4	NP_004983.1
	MECP2	NM_001316337.2		c.407C>T	p.Ser136Leu	missense	Exon 5 of 5	NP_001303266.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MECP2	ENST00000453960.7	TSL:1 MANE Select	c.722C>T	p.Ser241Leu	missense	Exon 3 of 3	ENSP00000395535.2
	MECP2	ENST00000303391.11	TSL:1 MANE Plus Clinical	c.686C>T	p.Ser229Leu	missense	Exon 4 of 4	ENSP00000301948.6
	MECP2	ENST00000630151.3	TSL:5	c.686C>T	p.Ser229Leu	missense	Exon 4 of 4	ENSP00000486089.2

Frequencies

GnomAD3 genomes AF: 0.000173 AC: 19 AN: 109871 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.0000999

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000191

Gnomad ASJ AF: 0.000381

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000248

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000158 AC: 29 AN: 183449 AF XY: 0.000133

Gnomad AFR exome AF: 0.0000760

Gnomad AMR exome AF: 0.0000729

Gnomad ASJ exome AF: 0.000134

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000625

Gnomad NFE exome AF: 0.000256

Gnomad OTH exome AF: 0.000441

GnomAD4 exome AF: 0.000344 AC: 378 AN: 1098215 Hom.: 0 Cov.: 36 AF XY: 0.000316 AC XY: 115 AN XY: 363571

African (AFR) AF: 0.000151 AC: 4 AN: 26403

American (AMR) AF: 0.0000568 AC: 2 AN: 35207

Ashkenazi Jewish (ASJ) AF: 0.000310 AC: 6 AN: 19386

East Asian (EAS) AF: 0.0000662 AC: 2 AN: 30206

South Asian (SAS) AF: 0.0000554 AC: 3 AN: 54144

European-Finnish (FIN) AF: 0.0000740 AC: 3 AN: 40533

Middle Eastern (MID) AF: 0.000483 AC: 2 AN: 4137

European-Non Finnish (NFE) AF: 0.000397 AC: 334 AN: 842102

Other (OTH) AF: 0.000477 AC: 22 AN: 46097

GnomAD4 genome AF: 0.000173 AC: 19 AN: 109871 Hom.: 0 Cov.: 23 AF XY: 0.000248 AC XY: 8 AN XY: 32207

African (AFR) AF: 0.0000999 AC: 3 AN: 30017

American (AMR) AF: 0.000191 AC: 2 AN: 10462

Ashkenazi Jewish (ASJ) AF: 0.000381 AC: 1 AN: 2625

East Asian (EAS) AF: 0.00 AC: 0 AN: 3472

South Asian (SAS) AF: 0.00 AC: 0 AN: 2514

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5935

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 239

European-Non Finnish (NFE) AF: 0.000248 AC: 13 AN: 52459

Other (OTH) AF: 0.00 AC: 0 AN: 1478

Alfa AF: 0.000172 Hom.: 4

Bravo AF: 0.000234

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000149 AC: 1

ExAC AF: 0.000148 AC: 18

EpiCase AF: 0.000327

EpiControl AF: 0.000119

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	2	not specified (2)
-	-	1	Intellectual disability (1)
-	-	1	Rett syndrome (1)
-	-	1	Severe neonatal-onset encephalopathy with microcephaly (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.096
BayesDel_addAF	Uncertain	0.039	T
BayesDel_noAF	Uncertain	0.11
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.51	D
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Uncertain	0.96	D
M_CAP	Pathogenic	0.74	D
MetaRNN	Benign	0.37	T
MetaSVM	Uncertain	-0.039	T
MutationAssessor	Benign	1.2	L
PhyloP100		4.4
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-1.6	N
REVEL	Uncertain	0.38
Sift	Uncertain	0.0030	D
Sift4G	Benign	0.079	T
Polyphen		0.81	P
Vest4		0.29
MVP		0.99
ClinPred		0.053	T
GERP RS		5.5
Varity_R		0.15
gMVP		0.40
Mutation Taster		=89/11	polymorphism

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: rs61749739; hg19: chrX-153296593; COSMIC: COSV57655216; COSMIC: COSV57655216;