chr22-30941917-C-A

Variant names:

• chr22-30941917-C-A
• rs893153652
• NM_001303256.3:c.672G>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001303256.3(MORC2):​c.672G>T​(p.Gln224His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. 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. Q224R) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MORC2 NM_001303256.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.27
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• Charcot-Marie-Tooth disease axonal type 2Z

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Orphanet, Labcorp Genetics (formerly Invitae)
• developmental delay, impaired growth, dysmorphic facies, and axonal neuropathy

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• Leigh syndrome

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.1965208).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001303256.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MORC2	NM_001303256.3	MANE Select	c.672G>T	p.Gln224His	missense	Exon 8 of 26	NP_001290185.1
	MORC2	NM_001303257.2		c.672G>T	p.Gln224His	missense	Exon 8 of 26	NP_001290186.1
	MORC2	NM_014941.3		c.486G>T	p.Gln162His	missense	Exon 9 of 27	NP_055756.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MORC2	ENST00000397641.8	TSL:5 MANE Select	c.672G>T	p.Gln224His	missense	Exon 8 of 26	ENSP00000380763.2
	MORC2	ENST00000215862.8	TSL:1	c.486G>T	p.Gln162His	missense	Exon 9 of 27	ENSP00000215862.4
	MORC2	ENST00000924805.1		c.672G>T	p.Gln224His	missense	Exon 8 of 26	ENSP00000594864.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Charcot-Marie-Tooth disease axonal type 2Z (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Benign	-0.057	T
BayesDel_noAF	Benign	-0.32
CADD	Uncertain	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.085	T
Eigen	Benign	-0.60
Eigen_PC	Benign	-0.47
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.86	D
M_CAP	Benign	0.032	D
MetaRNN	Benign	0.20	T
MetaSVM	Benign	-0.81	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		2.3
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-1.8	N
REVEL	Benign	0.14
Sift	Benign	0.13	T
Sift4G	Benign	0.093	T
Polyphen		0.0060	B
Vest4		0.44
MutPred		0.28		Gain of glycosylation at S229 (P = 0.1422)
MVP		0.55
MPC		1.7
ClinPred		0.67	D
GERP RS		1.9
Varity_R		0.096
gMVP		0.72
Mutation Taster		=60/40	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.13		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs893153652; hg19: chr22-31337904;