chr22-30939666-C-T
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Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PP2BS2
The NM_001303256.3(MORC2):c.1028G>A(p.Arg343His) variant causes a missense change. The variant allele was found at a frequency of 0.00000684 in 1,461,822 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R343C) has been classified as Uncertain significance.
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000068 ( 0 hom. )
Consequence
MORC2
NM_001303256.3 missense
NM_001303256.3 missense
Scores
4
8
7
Clinical Significance
Conservation
PhyloP100: 5.20
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 Likely_benign. Variant got -3 ACMG points.
PP2
Missense variant where missense usually causes diseases, MORC2
BS2
High AC in GnomAdExome4 at 10 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MORC2 | NM_001303256.3 | c.1028G>A | p.Arg343His | missense_variant | 12/26 | ENST00000397641.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MORC2 | ENST00000397641.8 | c.1028G>A | p.Arg343His | missense_variant | 12/26 | 5 | NM_001303256.3 | P1 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 genomes
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32
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251090Hom.: 0 AF XY: 0.00000737 AC XY: 1AN XY: 135714
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GnomAD4 exome AF: 0.00000684 AC: 10AN: 1461822Hom.: 0 Cov.: 31 AF XY: 0.00000825 AC XY: 6AN XY: 727222
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GnomAD4 genome Cov.: 32
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32
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Charcot-Marie-Tooth disease axonal type 2Z Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jun 01, 2022 | ClinVar contains an entry for this variant (Variation ID: 475604). This variant has not been reported in the literature in individuals affected with MORC2-related conditions. This variant is present in population databases (rs753651729, gnomAD 0.003%). This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 343 of the MORC2 protein (p.Arg343His). 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. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Jan 12, 2023 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Uncertain
T
BayesDel_noAF
Benign
CADD
Pathogenic
DANN
Pathogenic
DEOGEN2
Benign
T;.
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;D
M_CAP
Benign
T
MetaRNN
Uncertain
D;D
MetaSVM
Benign
T
MutationAssessor
Uncertain
M;.
MutationTaster
Benign
D;D
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D;D
REVEL
Benign
Sift
Uncertain
D;D
Sift4G
Uncertain
D;D
Polyphen
D;.
Vest4
MutPred
Gain of helix (P = 0.0496);.;
MVP
MPC
2.2
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
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Calibrated prediction
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Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at