rs1555938796

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM2PP2PP3_ModeratePP5_Very_Strong

The NM_001303256.3(MORC2):​c.1181A>G​(p.Tyr394Cys) 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 Likely pathogenic (★★).

Frequency

Genomes: not found (cov: 32)

Consequence

MORC2
NM_001303256.3 missense

Scores

11
6
2

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5U:1

Conservation

PhyloP100: 7.65
Variant links:
Genes affected
MORC2 (HGNC:23573): (MORC family CW-type zinc finger 2) This gene encodes a member of the Microrchidia (MORC) protein superfamily. The encoded protein is known to regulate the condensation of heterochromatin in response to DNA damage and play a role in repressing transcription. The protein has been found to regulate the activity of ATP citrate lyase via specific interaction with this enzyme in the cytosol of lipogenic breast cancer cells. The protein also plays a role in lipogenesis and adipocyte differentiation. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Feb 2016]

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 13 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP2
Missense variant in gene, where missense usually causes diseases (based on misZ statistic), MORC2. . Gene score misZ 3.2251 (greater than the threshold 3.09). Trascript score misZ 4.4393 (greater than threshold 3.09). GenCC has associacion of gene with Leigh syndrome, Charcot-Marie-Tooth disease axonal type 2Z, developmental delay, impaired growth, dysmorphic facies, and axonal neuropathy.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.899
PP5
Variant 22-30938098-T-C is Pathogenic according to our data. Variant chr22-30938098-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 432089.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-30938098-T-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
MORC2NM_001303256.3 linkuse as main transcriptc.1181A>G p.Tyr394Cys missense_variant 13/26 ENST00000397641.8 NP_001290185.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
MORC2ENST00000397641.8 linkuse as main transcriptc.1181A>G p.Tyr394Cys missense_variant 13/265 NM_001303256.3 ENSP00000380763 P1Q9Y6X9-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
34
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:5Uncertain:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Charcot-Marie-Tooth disease axonal type 2Z Pathogenic:3
Pathogenic, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpDec 18, 2023This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 394 of the MORC2 protein (p.Tyr394Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of MORC2-related conditions (PMID: 28771897, 32693025). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 432089). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt MORC2 protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitterclinical testingInstitute of Human Genetics Munich, Klinikum Rechts Der Isar, TU MünchenApr 18, 2018- -
Likely pathogenic, criteria provided, single submitterclinical testingInstitute of Immunology and Genetics KaiserslauternSep 12, 2022ACMG Criteria: PS2, PM2, PP3, PP5; Variant was found in heterozygous state. De novo-status was confirmed via in-house segregation analysis. -
not provided Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingGeneDxSep 17, 2021In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 34189813, 28771897, 32693025, 33098801) -
MORC2-related disorder Pathogenic:1
Pathogenic, no assertion criteria providedclinical testingPreventionGenetics, part of Exact SciencesFeb 17, 2024The MORC2 c.1181A>G variant is predicted to result in the amino acid substitution p.Tyr394Cys. This variant was reported in individuals with neurodevelopmental disorders or suspected Charcot-Marie-Tooth disease; in several, this variant arose de novo (see, for example, Guillen Sacoto et al. 2020. PubMed ID: 32693025; Zech et al. 2020. PubMed ID: 33098801, supplementary data, reported as p.Tyr332Cys; Sivera et al. 2021. PubMed ID: 34189813; Frongia et al. 2021. PubMed ID: 34630290). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as pathogenic. -
Inborn genetic diseases Uncertain:1
Uncertain significance, flagged submissionclinical testingAmbry GeneticsJan 10, 2018- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.90
BayesDel_addAF
Pathogenic
0.27
D
BayesDel_noAF
Pathogenic
0.15
CADD
Uncertain
25
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.54
D;.
Eigen
Pathogenic
0.83
Eigen_PC
Pathogenic
0.80
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.94
D;D
M_CAP
Uncertain
0.17
D
MetaRNN
Pathogenic
0.90
D;D
MetaSVM
Benign
-0.74
T
MutationAssessor
Pathogenic
2.9
M;.
MutationTaster
Benign
1.0
D;D
PrimateAI
Pathogenic
0.90
D
PROVEAN
Pathogenic
-7.3
D;D
REVEL
Pathogenic
0.81
Sift
Uncertain
0.0010
D;D
Sift4G
Uncertain
0.0070
D;D
Polyphen
1.0
D;.
Vest4
0.92
MutPred
0.73
Loss of phosphorylation at Y394 (P = 0.1271);.;
MVP
0.75
MPC
2.2
ClinPred
1.0
D
GERP RS
5.6
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.88
gMVP
0.95

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.17
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.

Other links and lift over

dbSNP: rs1555938796; hg19: chr22-31334085; API