rs61751363

Variant names:

• chrX-154030502-G-A
• rs61751363
• NM_001110792.2:c.1362C>T

Your query was ambiguous. Multiple possible variants found:

• chrX-154030502-G-A
• chrX-154030502-G-C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001110792.2(MECP2):​c.1362C>T​(p.Thr454Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000236 in 1,209,794 control chromosomes in the GnomAD database, including 1 homozygotes. There are 100 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. T454T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00023 (0 hom., 6 hem., cov: 23)
  • Exomes 𝑓: 0.00024 (1 hom. 94 hem.)
• Consequence: MECP2 NM_001110792.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.0660
• Publications: 4 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant X-154030502-G-A is Benign according to our data. Variant chrX-154030502-G-A is described in ClinVar as Benign. ClinVar VariationId is 143463.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.066 with no splicing effect.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000233 (26/111609) while in subpopulation EAS AF = 0.0048 (17/3542). AF 95% confidence interval is 0.00306. There are 0 homozygotes in GnomAd4. There are 6 alleles in the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check.
• BS2: High AC in GnomAd4 at 26 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MECP2	NM_001110792.2	MANE Select	c.1362C>T	p.Thr454Thr	synonymous	Exon 3 of 3	NP_001104262.1	A0A140VKC4
	MECP2	NM_004992.4	MANE Plus Clinical	c.1326C>T	p.Thr442Thr	synonymous	Exon 4 of 4	NP_004983.1	D3YJ43
	MECP2	NM_001316337.2		c.1047C>T	p.Thr349Thr	synonymous	Exon 5 of 5	NP_001303266.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MECP2	ENST00000453960.7	TSL:1 MANE Select	c.1362C>T	p.Thr454Thr	synonymous	Exon 3 of 3	ENSP00000395535.2	P51608-2
	MECP2	ENST00000303391.11	TSL:1 MANE Plus Clinical	c.1326C>T	p.Thr442Thr	synonymous	Exon 4 of 4	ENSP00000301948.6	P51608-1
	MECP2	ENST00000630151.3	TSL:5	c.1326C>T	p.Thr442Thr	synonymous	Exon 4 of 4	ENSP00000486089.2	P51608-1

Frequencies

GnomAD3 genomes AF: 0.000233 AC: 26 AN: 111557 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000948

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00478

Gnomad SAS AF: 0.000381

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000578 AC: 106 AN: 183330 AF XY: 0.000693

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000365

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00642

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000855

Gnomad OTH exome AF: 0.000662

GnomAD4 exome AF: 0.000236 AC: 259 AN: 1098185 Hom.: 1 Cov.: 32 AF XY: 0.000259 AC XY: 94 AN XY: 363553

African (AFR) AF: 0.0000379 AC: 1 AN: 26400

American (AMR) AF: 0.0000284 AC: 1 AN: 35207

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19385

East Asian (EAS) AF: 0.00639 AC: 193 AN: 30206

South Asian (SAS) AF: 0.000203 AC: 11 AN: 54148

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40489

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4135

European-Non Finnish (NFE) AF: 0.0000416 AC: 35 AN: 842118

Other (OTH) AF: 0.000390 AC: 18 AN: 46097

GnomAD4 genome AF: 0.000233 AC: 26 AN: 111609 Hom.: 0 Cov.: 23 AF XY: 0.000178 AC XY: 6 AN XY: 33779

African (AFR) AF: 0.00 AC: 0 AN: 30750

American (AMR) AF: 0.0000947 AC: 1 AN: 10559

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2643

East Asian (EAS) AF: 0.00480 AC: 17 AN: 3542

South Asian (SAS) AF: 0.000382 AC: 1 AN: 2615

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6054

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

European-Non Finnish (NFE) AF: 0.000132 AC: 7 AN: 53018

Other (OTH) AF: 0.00 AC: 0 AN: 1524

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.000223

EpiCase AF: 0.000109

EpiControl AF: 0.000119

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.84
DANN	Benign	0.73
PhyloP100		0.066
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Mutation Taster		=100/0	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: rs61751363; hg19: chrX-153295953;