Variant rs61753966 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001110792.2(MECP2):c.1270G>T(p.Val424Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000913 in 1,095,409 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as not provided (no stars).

Frequency

Genomes: not found (cov: 22)

Exomes 𝑓: 9.1e-7 ( 0 hom. 0 hem. )

Consequence

MECP2
NM_001110792.2 missense

Scores

Clinical Significance

not provided no classification provided O:1

Conservation

PhyloP100: -0.363

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 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.14329726).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MECP2	NM_001110792.2 linkuse as main transcript	c.1270G>T	p.Val424Phe	missense_variant	3/3	ENST00000453960.7	NP_001104262.1
MECP2	NM_004992.4 linkuse as main transcript	c.1234G>T	p.Val412Phe	missense_variant	4/4	ENST00000303391.11	NP_004983.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MECP2	ENST00000453960.7 linkuse as main transcript	c.1270G>T	p.Val424Phe	missense_variant	3/3	1	NM_001110792.2	ENSP00000395535		P51608-2
MECP2	ENST00000303391.11 linkuse as main transcript	c.1234G>T	p.Val412Phe	missense_variant	4/4	1	NM_004992.4	ENSP00000301948	P1	P51608-1
MECP2	ENST00000628176.2 linkuse as main transcript	c.*606G>T		3_prime_UTR_variant	5/5	3		ENSP00000486978
MECP2	ENST00000407218.5 linkuse as main transcript			downstream_gene_variant		5		ENSP00000384865

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000555

AC:

AN:

180258

Hom.:

AF XY:

0.00

AC XY:

AN XY:

65744

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 SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

9.13e-7

AC:

AN:

1095409

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

361687

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000284

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.0000189

ClinVar

Significance: not provided

Submissions summary: Other:1

Revision: no classification provided

LINK: link

Submissions by phenotype

MECP2-related disorder

Other:1

not provided, no classification provided

phenotyping only

GenomeConnect, ClinGen

Variant interpretted as Uncertain significance and reported on 01-04-2019 by Lab or GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Uncertain

0.030

BayesDel_noAF

Uncertain

-0.080

CADD

Benign

6.3

DANN

Benign

0.97

DEOGEN2

Benign

0.38

T;.

FATHMM_MKL

Benign

0.11

LIST_S2

Uncertain

0.90

D;D

M_CAP

Uncertain

0.14

MetaRNN

Benign

0.14

T;T

MetaSVM

Benign

-0.55

MutationAssessor

Benign

0.55

N;.

MutationTaster

Benign

1.0

N;N

PrimateAI

Uncertain

0.49

PROVEAN

Benign

-1.2

N;N

REVEL

Uncertain

0.52

Sift

Uncertain

0.019

D;D

Sift4G

Benign

0.13

T;T

Polyphen

0.067

B;B

Vest4

0.090

MutPred

0.076

Gain of helix (P = 0.132);.;

MVP

0.99

ClinPred

0.14

GERP RS

1.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.22

gMVP

0.26

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over