22-30926838-C-G

Variant names:

• chr22-30926838-C-G
• rs12330040
• NM_001303256.3:c.3064G>C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP2

The NM_001303256.3(MORC2):​c.3064G>C​(p.Ala1022Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 31)
• Consequence: MORC2 NM_001303256.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.30

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 3 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MORC2	NM_001303256.3	c.3064G>C	p.Ala1022Pro	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.3064G>C	p.Ala1022Pro	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

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Uncertain	0.10	D
BayesDel_noAF	Benign	-0.090
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.079	T;T;.
Eigen	Uncertain	0.28
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.84	T;T;T
M_CAP	Benign	0.026	D
MetaRNN	Uncertain	0.44	T;T;T
MetaSVM	Benign	-0.88	T
MutationAssessor	Benign	0.90	L;.;.
PrimateAI	Pathogenic	0.87	D
PROVEAN	Benign	-2.2	N;D;N
REVEL	Uncertain	0.32
Sift	Uncertain	0.0060	D;D;D
Sift4G	Benign	0.12	T;D;T
Polyphen		0.99	D;.;.
Vest4		0.75
MutPred		0.29		Loss of stability (P = 0.0422);.;.;
MVP		0.47
MPC		1.4
ClinPred		0.90	D
GERP RS		4.8
Varity_R		0.79
gMVP		0.53

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs12330040; hg19: chr22-31322825;