X-154030918-T-G

Position:

• chrX-154030918-T-G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Moderate PP5_Moderate

The NM_001110792.2(MECP2):​c.946A>C​(p.Lys316Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 23)
• Consequence: MECP2 NM_001110792.2 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 7.24

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.906
• PP5: Variant X-154030918-T-G is Pathogenic according to our data. Variant chrX-154030918-T-G is described in ClinVar as [Pathogenic]. Clinvar id is 420031.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MECP2	NM_001110792.2	c.946A>C	p.Lys316Gln	missense_variant	3/3	ENST00000453960.7	NP_001104262.1
MECP2	NM_004992.4	c.910A>C	p.Lys304Gln	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	c.946A>C	p.Lys316Gln	missense_variant	3/3	1	NM_001110792.2	ENSP00000395535.2
MECP2	ENST00000303391.11	c.910A>C	p.Lys304Gln	missense_variant	4/4	1	NM_004992.4	ENSP00000301948.6

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Mar 14, 2017

The K304Q variant in the MECP2 gene has been reported previously in an individualwith classic Rett syndrome (Charman et al., 2005). The K304Q variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server. The K304Q variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved across species. Additionally, a different missense variant (K304E) at the same and multiple missense variants in nearby residues have been reported in Human Gene Mutation Database in association with Rett Syndrome (Philippe et al., 2006; Stenson et al., 2014), supporting the functional importance of this region of the protein, Therefore, the presence of K304Q is consistent with the diagnosis of Rett syndrome in this individual. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.59	D
BayesDel_noAF	Pathogenic	0.60
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.57	D;.
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.96	D;D
M_CAP	Pathogenic	0.96	D
MetaRNN	Pathogenic	0.91	D;D
MetaSVM	Pathogenic	0.88	D
MutationAssessor	Uncertain	2.2	M;.
PrimateAI	Pathogenic	0.82	D
PROVEAN	Benign	-0.88	N;N
REVEL	Pathogenic	0.83
Sift	Pathogenic	0.0	D;D
Sift4G	Benign	0.19	T;T
Polyphen		1.0	D;D
Vest4		0.49
MutPred		0.86		Loss of methylation at K304 (P = 0.0025);.;
MVP		1.0
ClinPred		0.97	D
GERP RS		5.1
Varity_R		0.78
gMVP		0.98

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

Other links and lift over

dbSNP: rs61751440; hg19: chrX-153296369;