rs61748423

Variant names:

• chrX-154030931-G-A
• rs61748423
• NM_001110792.2:c.933C>T

Your query was ambiguous. Multiple possible variants found:

• chrX-154030931-G-A
• chrX-154030931-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.933C>T​(p.Thr311Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00298 in 1,210,623 control chromosomes in the GnomAD database, including 5 homozygotes. There are 1,171 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 0.0020 (1 hom., 58 hem., cov: 23)
  • Exomes 𝑓: 0.0031 (4 hom. 1113 hem.)
• Consequence: MECP2 NM_001110792.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:14
• Conservation: PhyloP100: -0.609
• 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: 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 (MetaRNN=0.008170664).
• BP6: Variant X-154030931-G-A is Benign according to our data. Variant chrX-154030931-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 95205.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.609 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00203 (228/112391) while in subpopulation NFE AF = 0.00292 (155/53129). AF 95% confidence interval is 0.00254. There are 1 homozygotes in GnomAd4. There are 58 alleles in the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check.
• BS2: High AC in GnomAd4 at 228 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.933C>T	p.Thr311Thr	synonymous	Exon 3 of 3	NP_001104262.1	A0A140VKC4
	MECP2	NM_004992.4	MANE Plus Clinical	c.897C>T	p.Thr299Thr	synonymous	Exon 4 of 4	NP_004983.1	D3YJ43
	MECP2	NM_001316337.2		c.618C>T	p.Thr206Thr	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.933C>T	p.Thr311Thr	synonymous	Exon 3 of 3	ENSP00000395535.2	P51608-2
	MECP2	ENST00000303391.11	TSL:1 MANE Plus Clinical	c.897C>T	p.Thr299Thr	synonymous	Exon 4 of 4	ENSP00000301948.6	P51608-1
	MECP2	ENST00000630151.3	TSL:5	c.897C>T	p.Thr299Thr	synonymous	Exon 4 of 4	ENSP00000486089.2	P51608-1

Frequencies

GnomAD3 genomes AF: 0.00203 AC: 228 AN: 112339 Hom.: 1 Cov.: 23

Gnomad AFR AF: 0.000485

Gnomad AMI AF: 0.0630

Gnomad AMR AF: 0.000747

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000560

Gnomad SAS AF: 0.000727

Gnomad FIN AF: 0.000163

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00292

Gnomad OTH AF: 0.00133

GnomAD2 exomes AF: 0.00180 AC: 330 AN: 183486 AF XY: 0.00166

Gnomad AFR exome AF: 0.000304

Gnomad AMR exome AF: 0.000911

Gnomad ASJ exome AF: 0.000134

Gnomad EAS exome AF: 0.000505

Gnomad FIN exome AF: 0.000437

Gnomad NFE exome AF: 0.00328

Gnomad OTH exome AF: 0.000883

GnomAD4 exome AF: 0.00307 AC: 3376 AN: 1098232 Hom.: 4 Cov.: 35 AF XY: 0.00306 AC XY: 1113 AN XY: 363590

African (AFR) AF: 0.000985 AC: 26 AN: 26401

American (AMR) AF: 0.000937 AC: 33 AN: 35207

Ashkenazi Jewish (ASJ) AF: 0.000103 AC: 2 AN: 19386

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

South Asian (SAS) AF: 0.000739 AC: 40 AN: 54145

European-Finnish (FIN) AF: 0.000469 AC: 19 AN: 40526

Middle Eastern (MID) AF: 0.000725 AC: 3 AN: 4137

European-Non Finnish (NFE) AF: 0.00370 AC: 3113 AN: 842127

Other (OTH) AF: 0.00267 AC: 123 AN: 46097

GnomAD4 genome AF: 0.00203 AC: 228 AN: 112391 Hom.: 1 Cov.: 23 AF XY: 0.00168 AC XY: 58 AN XY: 34559

African (AFR) AF: 0.000484 AC: 15 AN: 31006

American (AMR) AF: 0.000746 AC: 8 AN: 10729

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2651

East Asian (EAS) AF: 0.000562 AC: 2 AN: 3561

South Asian (SAS) AF: 0.000729 AC: 2 AN: 2742

European-Finnish (FIN) AF: 0.000163 AC: 1 AN: 6148

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 219

European-Non Finnish (NFE) AF: 0.00292 AC: 155 AN: 53129

Other (OTH) AF: 0.00131 AC: 2 AN: 1524

Alfa AF: 0.000798 Hom.: 7

Bravo AF: 0.00254

TwinsUK AF: 0.00216 AC: 8

ALSPAC AF: 0.00381 AC: 11

ESP6500AA AF: 0.000261 AC: 1

ESP6500EA AF: 0.00357 AC: 24

ExAC AF: 0.00178 AC: 216

EpiCase AF: 0.00453

EpiControl AF: 0.00338

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	4	not provided (4)
-	-	1	History of neurodevelopmental disorder (1)
-	-	1	Rett syndrome (1)
-	-	1	Rett syndrome;C0796222:X-linked intellectual disability-psychosis-macroorchidism syndrome;C1845336:Autism, susceptibility to, X-linked 3;C1846058:Syndromic X-linked intellectual disability Lubs type;C1968556:Severe neonatal-onset encephalopathy with microcephaly (1)
-	-	1	Severe neonatal-onset encephalopathy with microcephaly (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	2.9
DANN	Benign	0.75
DEOGEN2	Benign	0.086	T
FATHMM_MKL	Benign	0.22	N
LIST_S2	Benign	0.45	T
MetaRNN	Benign	0.0082	T
PhyloP100		-0.61
Sift4G	Uncertain	0.053	T
Vest4		0.39
MVP		0.77
GERP RS		2.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
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: rs61748423; hg19: chrX-153296382; COSMIC: COSV104409427; COSMIC: COSV104409427;