22-30926820-T-C

Variant names:

• chr22-30926820-T-C
• NM_001303256.3:c.3082A>G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_001303256.3(MORC2):​c.3082A>G​(p.Ile1028Val) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: MORC2 NM_001303256.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.66

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]

MORC2-AS1 (HGNC:26662): (MORC2 antisense RNA 1)

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the MORC2 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 25 curated pathogenic missense variants (we use a threshold of 10). The gene has 13 curated benign missense variants. Gene score misZ: 3.2251 (above the threshold of 3.09). Trascript score misZ: 4.4393 (above the threshold of 3.09). GenCC associations: The gene is linked to Leigh syndrome, Charcot-Marie-Tooth disease axonal type 2Z, developmental delay, impaired growth, dysmorphic facies, and axonal neuropathy.
• BP4: Computational evidence support a benign effect (MetaRNN=0.10681996).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MORC2	NM_001303256.3	c.3082A>G	p.Ile1028Val	missense_variant	Exon 26 of 26	ENST00000397641.8	NP_001290185.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MORC2	ENST00000397641.8	c.3082A>G	p.Ile1028Val	missense_variant	Exon 26 of 26	5	NM_001303256.3	ENSP00000380763.2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Charcot-Marie-Tooth disease axonal type 2Z Uncertain:1

Aug 28, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 1028 of the MORC2 protein (p.Ile1028Val). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with MORC2-related conditions. 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 not 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	21
DANN	Uncertain	0.98
DEOGEN2	Benign	0.038	T;T;.
Eigen	Benign	-0.35
Eigen_PC	Benign	-0.10
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.81	T;D;T
M_CAP	Benign	0.0031	T
MetaRNN	Benign	0.11	T;T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.0	N;.;.
PrimateAI	Uncertain	0.78	T
PROVEAN	Benign	-0.49	N;N;N
REVEL	Benign	0.097
Sift	Benign	0.43	T;T;T
Sift4G	Benign	0.34	T;T;T
Polyphen		0.0010	B;.;.
Vest4		0.31
MutPred		0.14		Loss of methylation at K1030 (P = 0.0775);.;.;
MVP		0.14
MPC		0.73
ClinPred		0.35	T
GERP RS		4.7
Varity_R		0.073
gMVP		0.088

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr22-31322807;