NM_001110792.2:c.1241C>A

Variant names:

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_ModerateBP6_ModerateBS2

The NM_001110792.2(MECP2):c.1241C>A(p.Pro414His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000773 in 1,202,949 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 30 hemizygotes in GnomAD. In-silico tool predicts 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. P414T) has been classified as Benign.

Frequency

Genomes: 𝑓 0.000055 ( 0 hom., 3 hem., cov: 21)

Exomes 𝑓: 0.000080 ( 0 hom. 27 hem. )

Consequence

MECP2
NM_001110792.2 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 3.30

Publications

5 publications found

Variant links:

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

MECP2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.1299018).

BP6

Variant X-154030623-G-T is Benign according to our data. Variant chrX-154030623-G-T is described in ClinVar as Likely_benign. ClinVar VariationId is 952492.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High AC in GnomAd4 at 6 XL,Unknown,AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MECP2	NM_001110792.2 link	c.1241C>A	p.Pro414His	missense_variant	Exon 3 of 3	ENST00000453960.7	NP_001104262.1
MECP2	NM_004992.4 link	c.1205C>A	p.Pro402His	missense_variant	Exon 4 of 4	ENST00000303391.11	NP_004983.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MECP2	ENST00000453960.7 link	c.1241C>A	p.Pro414His	missense_variant	Exon 3 of 3	1	NM_001110792.2	ENSP00000395535.2
MECP2	ENST00000303391.11 link	c.1205C>A	p.Pro402His	missense_variant	Exon 4 of 4	1	NM_004992.4	ENSP00000301948.6

Frequencies

GnomAD3 genomes

AF:

0.0000551

AC:

AN:

108831

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000336

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000961

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000339

AC:

AN:

176820

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000365

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000633

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000795

AC:

AN:

1094118

Hom.:

Cov.:

AF XY:

0.0000747

AC XY:

AN XY:

361230

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26395

American (AMR)

AF:

0.0000284

AC:

AN:

35186

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19380

East Asian (EAS)

AF:

0.0000331

AC:

AN:

30201

South Asian (SAS)

AF:

0.00

AC:

AN:

54128

European-Finnish (FIN)

AF:

0.00

AC:

AN:

37042

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3936

European-Non Finnish (NFE)

AF:

0.0000962

AC:

AN:

841827

Other (OTH)

AF:

0.0000869

AC:

AN:

46023

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.534

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000551

AC:

AN:

108831

Hom.:

Cov.:

AF XY:

0.0000963

AC XY:

AN XY:

31141

show subpopulations

African (AFR)

AF:

0.0000336

AC:

AN:

29764

American (AMR)

AF:

0.00

AC:

AN:

10253

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2606

East Asian (EAS)

AF:

0.00

AC:

AN:

3482

South Asian (SAS)

AF:

0.00

AC:

AN:

2459

European-Finnish (FIN)

AF:

0.00

AC:

AN:

5889

Middle Eastern (MID)

AF:

0.00

AC:

AN:

236

European-Non Finnish (NFE)

AF:

0.0000961

AC:

AN:

52022

Other (OTH)

AF:

0.00

AC:

AN:

1449

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000264

ExAC

AF:

0.00000825

AC:

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Severe neonatal-onset encephalopathy with microcephaly

Benign:1

Jul 11, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.098

BayesDel_addAF

Benign

-0.036

BayesDel_noAF

Benign

-0.10

CADD

Uncertain

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.30

T;.

FATHMM_MKL

Uncertain

0.77

LIST_S2

Uncertain

0.86

D;D

M_CAP

Uncertain

0.16

MetaRNN

Benign

0.13

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.14

N;.

PhyloP100

3.3

PrimateAI

Uncertain

0.49

PROVEAN

Benign

0.32

N;N

REVEL

Uncertain

0.41

Sift

Uncertain

0.0010

D;D

Sift4G

Uncertain

0.0030

D;D

Vest4

0.17

ClinPred

0.16

GERP RS

5.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.22

gMVP

0.24

Mutation Taster

=99/1

polymorphism

(source)

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over