rs61748397

Variant names:

• chrX-154031402-G-A
• rs61748397
• NM_001110792.2:c.462C>T

Your query was ambiguous. Multiple possible variants found:

• chrX-154031402-G-A
• chrX-154031402-G-C

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Moderate BP6_Very_Strong BS2

The NM_001110792.2(MECP2):​c.462C>T​(p.Phe154Phe) variant causes a synonymous change. The variant allele was found at a frequency of 0.000407 in 1,209,664 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 166 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 0.00020 (0 hom., 6 hem., cov: 23)
  • Exomes 𝑓: 0.00043 (0 hom. 160 hem.)
• Consequence: MECP2 NM_001110792.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 3.85
• Publications: 3 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.46).
• BP6: Variant X-154031402-G-A is Benign according to our data. Variant chrX-154031402-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 95195.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 22 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.462C>T	p.Phe154Phe	synonymous	Exon 3 of 3	NP_001104262.1
	MECP2	NM_004992.4	MANE Plus Clinical	c.426C>T	p.Phe142Phe	synonymous	Exon 4 of 4	NP_004983.1
	MECP2	NM_001386137.1		c.-135C>T		5_prime_UTR_premature_start_codon_gain	Exon 5 of 6	NP_001373066.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MECP2	ENST00000453960.7	TSL:1 MANE Select	c.462C>T	p.Phe154Phe	synonymous	Exon 3 of 3	ENSP00000395535.2
	MECP2	ENST00000303391.11	TSL:1 MANE Plus Clinical	c.426C>T	p.Phe142Phe	synonymous	Exon 4 of 4	ENSP00000301948.6
	MECP2	ENST00000630151.3	TSL:5	c.426C>T	p.Phe142Phe	synonymous	Exon 4 of 4	ENSP00000486089.2

Frequencies

GnomAD3 genomes AF: 0.000196 AC: 22 AN: 112095 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.000130

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000944

Gnomad ASJ AF: 0.000378

Gnomad EAS AF: 0.000278

Gnomad SAS AF: 0.000369

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000263

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000368 AC: 67 AN: 181868 AF XY: 0.000416

Gnomad AFR exome AF: 0.0000760

Gnomad AMR exome AF: 0.000292

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000505

Gnomad FIN exome AF: 0.000125

Gnomad NFE exome AF: 0.000398

Gnomad OTH exome AF: 0.000443

GnomAD4 exome AF: 0.000428 AC: 470 AN: 1097569 Hom.: 0 Cov.: 34 AF XY: 0.000441 AC XY: 160 AN XY: 362933

African (AFR) AF: 0.000341 AC: 9 AN: 26387

American (AMR) AF: 0.000369 AC: 13 AN: 35203

Ashkenazi Jewish (ASJ) AF: 0.000103 AC: 2 AN: 19383

East Asian (EAS) AF: 0.000563 AC: 17 AN: 30206

South Asian (SAS) AF: 0.000610 AC: 33 AN: 54132

European-Finnish (FIN) AF: 0.0000987 AC: 4 AN: 40531

Middle Eastern (MID) AF: 0.00121 AC: 5 AN: 4134

European-Non Finnish (NFE) AF: 0.000443 AC: 373 AN: 841521

Other (OTH) AF: 0.000304 AC: 14 AN: 46072

GnomAD4 genome AF: 0.000196 AC: 22 AN: 112095 Hom.: 0 Cov.: 23 AF XY: 0.000175 AC XY: 6 AN XY: 34243

African (AFR) AF: 0.000130 AC: 4 AN: 30820

American (AMR) AF: 0.0000944 AC: 1 AN: 10597

Ashkenazi Jewish (ASJ) AF: 0.000378 AC: 1 AN: 2646

East Asian (EAS) AF: 0.000278 AC: 1 AN: 3602

South Asian (SAS) AF: 0.000369 AC: 1 AN: 2710

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6102

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 240

European-Non Finnish (NFE) AF: 0.000263 AC: 14 AN: 53188

Other (OTH) AF: 0.00 AC: 0 AN: 1506

Alfa AF: 0.000422 Hom.: 8

Bravo AF: 0.000189

EpiCase AF: 0.000491

EpiControl AF: 0.000652

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	1	Inborn genetic diseases (1)
-	-	1	not provided (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	-0.46
CADD	Benign	11
DANN	Benign	0.73
PhyloP100		3.9
Mutation Taster		=97/3	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: rs61748397; hg19: chrX-153296853; COSMIC: COSV57653954; COSMIC: COSV57653954;