rs61753964

Variant names:

• chrX-154030613-G-A
• rs61753964
• NM_001110792.2:c.1251C>T

Your query was ambiguous. Multiple possible variants found:

• chrX-154030613-G-A
• chrX-154030613-G-C

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.1251C>T​(p.Pro417Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000823 in 1,203,270 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 31 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.000083 (0 hom., 3 hem., cov: 21)
  • Exomes 𝑓: 0.000082 (0 hom. 28 hem.)
• Consequence: MECP2 NM_001110792.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.734
• Publications: 1 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 (MetaRNN=0.028828979).
• BP6: Variant X-154030613-G-A is Benign according to our data. Variant chrX-154030613-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 143440.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.734 with no splicing effect.
• BS2: High AC in GnomAd4 at 9 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.1251C>T	p.Pro417Pro	synonymous	Exon 3 of 3	NP_001104262.1
	MECP2	NM_004992.4	MANE Plus Clinical	c.1215C>T	p.Pro405Pro	synonymous	Exon 4 of 4	NP_004983.1
	MECP2	NM_001316337.2		c.936C>T	p.Pro312Pro	synonymous	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.1251C>T	p.Pro417Pro	synonymous	Exon 3 of 3	ENSP00000395535.2
	MECP2	ENST00000303391.11	TSL:1 MANE Plus Clinical	c.1215C>T	p.Pro405Pro	synonymous	Exon 4 of 4	ENSP00000301948.6
	MECP2	ENST00000630151.3	TSL:5	c.1215C>T	p.Pro405Pro	synonymous	Exon 4 of 4	ENSP00000486089.2

Frequencies

GnomAD3 genomes AF: 0.0000828 AC: 9 AN: 108696 Hom.: 0 Cov.: 21

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000573

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000135

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000113 AC: 20 AN: 177436 AF XY: 0.000123

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000868

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000756

Gnomad OTH exome AF: 0.000225

GnomAD4 exome AF: 0.0000822 AC: 90 AN: 1094526 Hom.: 0 Cov.: 32 AF XY: 0.0000775 AC XY: 28 AN XY: 361410

African (AFR) AF: 0.00 AC: 0 AN: 26396

American (AMR) AF: 0.00 AC: 0 AN: 35196

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

East Asian (EAS) AF: 0.000430 AC: 13 AN: 30203

South Asian (SAS) AF: 0.0000739 AC: 4 AN: 54131

European-Finnish (FIN) AF: 0.0000269 AC: 1 AN: 37217

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3991

European-Non Finnish (NFE) AF: 0.0000772 AC: 65 AN: 841960

Other (OTH) AF: 0.000152 AC: 7 AN: 46048

GnomAD4 genome AF: 0.0000828 AC: 9 AN: 108744 Hom.: 0 Cov.: 21 AF XY: 0.0000966 AC XY: 3 AN XY: 31048

African (AFR) AF: 0.00 AC: 0 AN: 29824

American (AMR) AF: 0.00 AC: 0 AN: 10229

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2600

East Asian (EAS) AF: 0.000575 AC: 2 AN: 3480

South Asian (SAS) AF: 0.00 AC: 0 AN: 2412

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5869

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 217

European-Non Finnish (NFE) AF: 0.000135 AC: 7 AN: 51978

Other (OTH) AF: 0.00 AC: 0 AN: 1462

Alfa AF: 0.000162 Hom.: 0

Bravo AF: 0.0000831

ExAC AF: 0.000148 AC: 18

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Inborn genetic diseases (1)
-	-	1	not provided (1)
-	-	1	not specified (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	0.12
BayesDel_noAF	Benign	-0.56
CADD	Benign	7.5
DANN	Benign	0.65
DEOGEN2	Benign	0.099	T
FATHMM_MKL	Benign	0.59	D
LIST_S2	Benign	0.36	T
MetaRNN	Benign	0.029	T
MetaSVM	Benign	-0.83	T
PhyloP100		0.73
GERP RS		3.2
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: rs61753964; hg19: chrX-153296064;