X-154030594-C-T

Variant names:

• chrX-154030594-C-T
• rs61753966
• NM_001110792.2:c.1270G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001110792.2(MECP2):​c.1270G>A​(p.Val424Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000208 in 1,204,116 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 125 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V424A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00015 (0 hom., 4 hem., cov: 22)
  • Exomes 𝑓: 0.00021 (0 hom. 121 hem.)
• Consequence: MECP2 NM_001110792.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -0.363
• Publications: 4 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0071368515).
• BP6: Variant X-154030594-C-T is Benign according to our data. Variant chrX-154030594-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 143446.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000147 (16/108707) while in subpopulation SAS AF = 0.00249 (6/2407). AF 95% confidence interval is 0.00108. There are 0 homozygotes in GnomAd4. There are 4 alleles in the male GnomAd4 subpopulation. Median coverage is 22. This position passed quality control check.
• BS2: High AC in GnomAd4 at 16 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.1270G>A	p.Val424Ile	missense	Exon 3 of 3	NP_001104262.1	A0A140VKC4
	MECP2	NM_004992.4	MANE Plus Clinical	c.1234G>A	p.Val412Ile	missense	Exon 4 of 4	NP_004983.1	D3YJ43
	MECP2	NM_001316337.2		c.955G>A	p.Val319Ile	missense	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.1270G>A	p.Val424Ile	missense	Exon 3 of 3	ENSP00000395535.2	P51608-2
	MECP2	ENST00000303391.11	TSL:1 MANE Plus Clinical	c.1234G>A	p.Val412Ile	missense	Exon 4 of 4	ENSP00000301948.6	P51608-1
	MECP2	ENST00000630151.3	TSL:5	c.1234G>A	p.Val412Ile	missense	Exon 4 of 4	ENSP00000486089.2	P51608-1

Frequencies

GnomAD3 genomes AF: 0.000147 AC: 16 AN: 108662 Hom.: 0 Cov.: 22

Gnomad AFR AF: 0.0000671

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000983

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000289

Gnomad SAS AF: 0.00248

Gnomad FIN AF: 0.000176

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000958

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000449 AC: 81 AN: 180258 AF XY: 0.000684

Gnomad AFR exome AF: 0.0000767

Gnomad AMR exome AF: 0.000109

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000722

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000112

Gnomad OTH exome AF: 0.000444

GnomAD4 exome AF: 0.000214 AC: 234 AN: 1095409 Hom.: 0 Cov.: 32 AF XY: 0.000335 AC XY: 121 AN XY: 361687

African (AFR) AF: 0.0000758 AC: 2 AN: 26388

American (AMR) AF: 0.0000852 AC: 3 AN: 35199

Ashkenazi Jewish (ASJ) AF: 0.0000517 AC: 1 AN: 19359

East Asian (EAS) AF: 0.000530 AC: 16 AN: 30181

South Asian (SAS) AF: 0.00249 AC: 135 AN: 54132

European-Finnish (FIN) AF: 0.000104 AC: 4 AN: 38282

Middle Eastern (MID) AF: 0.000245 AC: 1 AN: 4079

European-Non Finnish (NFE) AF: 0.0000760 AC: 64 AN: 841749

Other (OTH) AF: 0.000174 AC: 8 AN: 46040

GnomAD4 genome AF: 0.000147 AC: 16 AN: 108707 Hom.: 0 Cov.: 22 AF XY: 0.000129 AC XY: 4 AN XY: 31119

African (AFR) AF: 0.0000670 AC: 2 AN: 29849

American (AMR) AF: 0.0000981 AC: 1 AN: 10190

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2604

East Asian (EAS) AF: 0.000290 AC: 1 AN: 3448

South Asian (SAS) AF: 0.00249 AC: 6 AN: 2407

European-Finnish (FIN) AF: 0.000176 AC: 1 AN: 5670

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 214

European-Non Finnish (NFE) AF: 0.0000958 AC: 5 AN: 52176

Other (OTH) AF: 0.00 AC: 0 AN: 1476

Alfa AF: 0.000109 Hom.: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000297 AC: 2

ExAC AF: 0.000494 AC: 60

EpiCase AF: 0.000109

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	3	not specified (3)
-	-	1	Inborn genetic diseases (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	0.075
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	3.3
DANN	Benign	0.93
DEOGEN2	Benign	0.30	T
FATHMM_MKL	Benign	0.017	N
LIST_S2	Benign	0.76	T
M_CAP	Uncertain	0.12	D
MetaRNN	Benign	0.0071	T
MetaSVM	Benign	-0.79	T
MutationAssessor	Benign	0.20	N
PhyloP100		-0.36
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-0.10	N
REVEL	Uncertain	0.39
Sift	Benign	0.59	T
Sift4G	Benign	0.26	T
Polyphen		0.0	B
Vest4		0.020
MVP		0.92
ClinPred		0.011	T
GERP RS		1.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.033
gMVP		0.11
Mutation Taster		=99/1	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: rs61753966; hg19: chrX-153296045; COSMIC: COSV57655267; COSMIC: COSV57655267;