rs61750246

Variant names:

• chrX-154030667-G-A
• rs61750246
• NM_001110792.2:c.1197C>T

Your query was ambiguous. Multiple possible variants found:

• chrX-154030667-G-A
• chrX-154030667-G-C
• chrX-154030667-G-T

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_001110792.2(MECP2):​c.1197C>T​(p.Pro399Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000122 in 1,088,399 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 48 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 has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000064 (0 hom., 2 hem., cov: 21)
  • Exomes 𝑓: 0.00012 (0 hom. 48 hem.)
  • Failed GnomAD Quality Control
• Consequence: MECP2 NM_001110792.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 1.27
• Publications: 5 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 -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.63).
• BP6: Variant X-154030667-G-A is Benign according to our data. Variant chrX-154030667-G-A is described in ClinVar as Benign. ClinVar VariationId is 95186.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.27 with no splicing effect.
• BS2: High AC in GnomAdExome4 at 133 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.1197C>T	p.Pro399Pro	synonymous	Exon 3 of 3	NP_001104262.1
	MECP2	NM_004992.4	MANE Plus Clinical	c.1161C>T	p.Pro387Pro	synonymous	Exon 4 of 4	NP_004983.1
	MECP2	NM_001316337.2		c.882C>T	p.Pro294Pro	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.1197C>T	p.Pro399Pro	synonymous	Exon 3 of 3	ENSP00000395535.2
	MECP2	ENST00000303391.11	TSL:1 MANE Plus Clinical	c.1161C>T	p.Pro387Pro	synonymous	Exon 4 of 4	ENSP00000301948.6
	MECP2	ENST00000630151.3	TSL:5	c.1161C>T	p.Pro387Pro	synonymous	Exon 4 of 4	ENSP00000486089.2

Frequencies

GnomAD3 genomes AF: 0.0000643 AC: 7 AN: 108851 Hom.: 0 Cov.: 21

Gnomad AFR AF: 0.0000671

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000195

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: 0.0000384

Gnomad OTH AF: 0.000685

GnomAD2 exomes AF: 0.000156 AC: 27 AN: 172947 AF XY: 0.000158

Gnomad AFR exome AF: 0.0000869

Gnomad AMR exome AF: 0.000147

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000733

Gnomad FIN exome AF: 0.000379

Gnomad NFE exome AF: 0.000156

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000122 AC: 133 AN: 1088399 Hom.: 0 Cov.: 35 AF XY: 0.000135 AC XY: 48 AN XY: 356397

African (AFR) AF: 0.0000381 AC: 1 AN: 26264

American (AMR) AF: 0.000114 AC: 4 AN: 35133

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19322

East Asian (EAS) AF: 0.0000332 AC: 1 AN: 30158

South Asian (SAS) AF: 0.000111 AC: 6 AN: 53932

European-Finnish (FIN) AF: 0.000326 AC: 12 AN: 36774

Middle Eastern (MID) AF: 0.000275 AC: 1 AN: 3634

European-Non Finnish (NFE) AF: 0.000123 AC: 103 AN: 837370

Other (OTH) AF: 0.000109 AC: 5 AN: 45812

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000643 AC: 7 AN: 108851 Hom.: 0 Cov.: 21 AF XY: 0.0000642 AC XY: 2 AN XY: 31143

African (AFR) AF: 0.0000671 AC: 2 AN: 29806

American (AMR) AF: 0.000195 AC: 2 AN: 10280

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2606

East Asian (EAS) AF: 0.00 AC: 0 AN: 3450

South Asian (SAS) AF: 0.00 AC: 0 AN: 2470

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5828

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 237

European-Non Finnish (NFE) AF: 0.0000384 AC: 2 AN: 52037

Other (OTH) AF: 0.000685 AC: 1 AN: 1460

Alfa AF: 0.0000434 Hom.: 0

Bravo AF: 0.0000869

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	3	Rett syndrome (3)
-	-	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	-0.63
CADD	Benign	4.0
DANN	Benign	0.47
PhyloP100		1.3
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: rs61750246; hg19: chrX-153296118; COSMIC: COSV57656782; COSMIC: COSV57656782;