rs61750245

Variant names:

• chrX-154031009-C-A
• rs61750245
• NM_001110792.2:c.855G>T

Your query was ambiguous. Multiple possible variants found:

• chrX-154031009-C-A
• chrX-154031009-C-G
• chrX-154031009-C-T

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.855G>T​(p.Gly285Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000542 in 1,210,680 control chromosomes in the GnomAD database, including 1 homozygotes. There are 227 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. G285G) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00057 (0 hom., 17 hem., cov: 23)
  • Exomes 𝑓: 0.00054 (1 hom. 210 hem.)
• Consequence: MECP2 NM_001110792.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -0.132
• Publications: 2 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=-0.51).
• BP6: Variant X-154031009-C-A is Benign according to our data. Variant chrX-154031009-C-A is described in ClinVar as Benign. ClinVar VariationId is 143706.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.132 with no splicing effect.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000569 (64/112491) while in subpopulation AMR AF = 0.000836 (9/10761). AF 95% confidence interval is 0.0006. There are 0 homozygotes in GnomAd4. There are 17 alleles in the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check.
• BS2: High AC in GnomAd4 at 64 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.855G>T	p.Gly285Gly	synonymous	Exon 3 of 3	NP_001104262.1	A0A140VKC4
	MECP2	NM_004992.4	MANE Plus Clinical	c.819G>T	p.Gly273Gly	synonymous	Exon 4 of 4	NP_004983.1	D3YJ43
	MECP2	NM_001316337.2		c.540G>T	p.Gly180Gly	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.855G>T	p.Gly285Gly	synonymous	Exon 3 of 3	ENSP00000395535.2	P51608-2
	MECP2	ENST00000303391.11	TSL:1 MANE Plus Clinical	c.819G>T	p.Gly273Gly	synonymous	Exon 4 of 4	ENSP00000301948.6	P51608-1
	MECP2	ENST00000630151.3	TSL:5	c.819G>T	p.Gly273Gly	synonymous	Exon 4 of 4	ENSP00000486089.2	P51608-1

Frequencies

GnomAD3 genomes AF: 0.000569 AC: 64 AN: 112438 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.000194

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000837

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000485

Gnomad MID AF: 0.00420

Gnomad NFE AF: 0.000790

Gnomad OTH AF: 0.00198

GnomAD2 exomes AF: 0.000461 AC: 84 AN: 182177 AF XY: 0.000490

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000219

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000722

Gnomad FIN exome AF: 0.000313

Gnomad NFE exome AF: 0.000874

Gnomad OTH exome AF: 0.000222

GnomAD4 exome AF: 0.000539 AC: 592 AN: 1098189 Hom.: 1 Cov.: 35 AF XY: 0.000578 AC XY: 210 AN XY: 363563

African (AFR) AF: 0.0000757 AC: 2 AN: 26403

American (AMR) AF: 0.000199 AC: 7 AN: 35207

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19384

East Asian (EAS) AF: 0.00 AC: 0 AN: 30205

South Asian (SAS) AF: 0.0000185 AC: 1 AN: 54146

European-Finnish (FIN) AF: 0.000247 AC: 10 AN: 40470

Middle Eastern (MID) AF: 0.000242 AC: 1 AN: 4137

European-Non Finnish (NFE) AF: 0.000660 AC: 556 AN: 842141

Other (OTH) AF: 0.000325 AC: 15 AN: 46096

GnomAD4 genome AF: 0.000569 AC: 64 AN: 112491 Hom.: 0 Cov.: 23 AF XY: 0.000490 AC XY: 17 AN XY: 34659

African (AFR) AF: 0.000194 AC: 6 AN: 30987

American (AMR) AF: 0.000836 AC: 9 AN: 10761

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2652

East Asian (EAS) AF: 0.00 AC: 0 AN: 3555

South Asian (SAS) AF: 0.00 AC: 0 AN: 2746

European-Finnish (FIN) AF: 0.000485 AC: 3 AN: 6186

Middle Eastern (MID) AF: 0.00461 AC: 1 AN: 217

European-Non Finnish (NFE) AF: 0.000790 AC: 42 AN: 53167

Other (OTH) AF: 0.00195 AC: 3 AN: 1536

Alfa AF: 0.000347 Hom.: 2

Bravo AF: 0.000540

EpiCase AF: 0.00120

EpiControl AF: 0.000711

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Rett syndrome (3)
-	-	2	not provided (2)
-	-	2	not specified (2)
-	-	1	Inborn genetic diseases (1)
-	-	1	MECP2-related disorder (1)
-	-	1	Severe neonatal-onset encephalopathy with microcephaly (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.51
CADD	Benign	1.7
DANN	Benign	0.64
PhyloP100		-0.13
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Mutation Taster		=100/0	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: rs61750245; hg19: chrX-153296460;