NM_001110792.2:c.508_510delACGinsCGT

Variant names:

• chrX-154031354-CGT-ACG
• NM_001110792.2:c.508_510delACGinsCGT
• MECP2 p.Thr170Arg

GermlineCancer (beta)

Variant summary

Our verdict is Pathogenic.

+14 Pathogenic

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 14 classification points (ACMG Germline Pathogenicity v2019). PS1_Very_StrongPM1PM2PM5

The NM_001110792.2(MECP2):c.508_510delACGinsCGT (p.Thr170Arg) variant causes a missense change. Note: allele frequency estimates from gnomAD may be inaccurate for this variant type (MNP or indel longer than 3 bp) due to technology limitations. The variant is absent from the gnomAD population database at sites with sufficient sequencing coverage. The affected nucleotide is highly conserved across species (PhyloP 100-way vertebrate score: 9.45). No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. A different missense at the same amino acid position has been reported as Pathogenic/Likely Pathogenic in ClinVar: p.T170K: Likely_pathogenic (ClinVar VariationId 1501953, 1 star) Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.T170= (synonymous): Likely_benign (ClinVar VariationId 2012560, 1 star); p.T170= (synonymous): Benign/Likely_benign (ClinVar VariationId 143591, 2 stars)

• Frequency: Genomes: not found (cov: 23)
• Consequence: MECP2 NM_001110792.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.45
• Publications: 0 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):

• Rett syndrome

  Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Labcorp Genetics (formerly Invitae), Orphanet, ClinGen, Ambry Genetics, PanelApp Australia
• 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

Classification according to ACMG Germline Pathogenicity v2019

Specifications for MECP2 are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Classification was made for transcript:

Our verdict: Pathogenic. The variant received 14 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PS1Same amino acid change as known pathogenic		Same AA change, ≥2-star ClinVar pathogenic — very strong (PS1); ClinVar contains 1 P/LP entry with the same amino acid change (highest review level: 2 stars).
	PM1Mutational hot spot or critical domain		Missense neighbourhood hotspot (≥2 P/LP within ±8 AA, OR ≥ 5 vs. background) — PM1; In-domain: 0 pathogenic, 0 benign rare missense variants.; ±8 AA neighbourhood: 27 pathogenic, 1 benign (OR vs. background: 91.7).
	PM2Absent/extremely low in population databases		Absent from gnomAD (AD/XL gene) — PM2; Absent from gnomAD at well-covered site (MOI: AD/XL) (threshold 0.0001) — PM2 moderate.
	PM5Novel missense at known pathogenic residue		Different pathogenic missense at same AA residue in ClinVar (PM5); ClinVar contains a germline Pathogenic/Likely Pathogenic entry at the same amino acid position with a different amino acid change: p.T170K: Likely_pathogenic (ClinVar VariationId 1501953, 1 star); Other variants at the same amino acid residue (not pathogenic): p.T170= (synonymous): Likely_benign (ClinVar VariationId 2012560, 1 star); p.T170= (synonymous): Benign/Likely_benign (ClinVar VariationId 143591, 2 stars)

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_001110792.2. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	MECP2 NM_001110792.2	MANE Select	c.508_510delACGinsCGT p.Thr170Arg	missense	N/A	Prot: NP_001104262.1 UniProt:
	MECP2 NM_004992.4	MANE Plus Clinical	c.472_474delACGinsCGT p.Thr158Arg	missense	N/A	Prot: NP_004983.1 UniProt:
	MECP2 NM_001316337.2		c.193_195delACGinsCGT p.Thr65Arg	missense	N/A	Prot: NP_001303266.1

MECP2 NM_001110792.2

MANE Select

HGVSc / HGVSpc.508_510delACGinsCGTp.Thr170Arg

Exon rankN/A

missense

Prot: NP_001104262.1UniProt: A0A140VKC4P51608-2

MECP2 NM_004992.4

MANE Plus Clinical

HGVSc / HGVSpc.472_474delACGinsCGTp.Thr158Arg

Exon rankN/A

missense

Prot: NP_004983.1UniProt: D3YJ43P51608-1

MECP2 NM_001316337.2

HGVSc / HGVSpc.193_195delACGinsCGTp.Thr65Arg

Exon rankN/A

missense

Prot: NP_001303266.1

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	MECP2 ENST00000453960.7	TSL:1MANE Select	c.508_510delACGinsCGT p.Thr170Arg	missense	N/A	Prot: ENSP00000395535.2 UniProt:
	MECP2 ENST00000303391.11	TSL:1MANE Plus Clinical	c.472_474delACGinsCGT p.Thr158Arg	missense	N/A	Prot: ENSP00000301948.6 UniProt:
	MECP2 ENST00000630151.3	TSL:5	c.472_474delACGinsCGT p.Thr158Arg	missense	N/A	Prot: ENSP00000486089.2 UniProt:

MECP2 ENST00000453960.7

TSL:1MANE Select

HGVSc / HGVSpc.508_510delACGinsCGTp.Thr170Arg

Exon rankN/A

missense

Prot: ENSP00000395535.2UniProt: P51608-2

MECP2 ENST00000303391.11

TSL:1MANE Plus Clinical

HGVSc / HGVSpc.472_474delACGinsCGTp.Thr158Arg

Exon rankN/A

missense

Prot: ENSP00000301948.6UniProt: P51608-1

MECP2 ENST00000630151.3

TSL:5

HGVSc / HGVSpc.472_474delACGinsCGTp.Thr158Arg

Exon rankN/A

missense

Prot: ENSP00000486089.2UniProt: A0A0D9SEX1P51608-1

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 2 sources Large-scale international reference populations
GnomAD3 genomes	AF:	AC:	Hom:	AN:	Cov:23
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:23

Showing 2 sources

Tested, but no data found:GnomAD4 exomeIf GnomAD4 is missing, the position is probably not covered by the project.

ClinVar

Not reported in ClinVar

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
PhyloP100	Pathogenic	9.5

Showing 1 of 1 scores

Splicing Scores

No splicing scores have been computed for this variant.

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

No MaveDB functional evidence found for this variant.

Other links and lift over

hg19: chrX-153296805;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar