rs864309503

Variant names:

• chr22-30941503-G-A
• rs864309503
• NM_001303256.3:c.754C>T

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PS3 PM2 PM5 PP3_Moderate PP5_Very_Strong

The NM_001303256.3(MORC2):​c.754C>T​(p.Arg252Trp) 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 pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV001934607: backed by functional studies (requires user validation) mentioned in 30624633, and also citing 29440755, 28771897, 28581500, 27105987, 27105897 and 5 more)." and additional evidence is available in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R252L) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MORC2 NM_001303256.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:17 U:2
• Conservation: PhyloP100: 3.14
• Publications: 24 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: Orphanet, Labcorp Genetics (formerly Invitae), ClinGen
• 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: Pathogenic. The variant received 18 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV001934607: backed by functional studies (requires user validation) mentioned in 30624633, and also citing 29440755, 28771897, 28581500, 27105987, 27105897 and 5 more).; SCV003930346: "functional studies provide supportive evidence that this variant has a damaging effect on the gene or gene product". PMID: 29440755, 28581500; SCV005626395: For functional characterization of the variant a vector, expressing MORC2 fused with Flag tag at C-terminal end, was created. Transfection of the plasmid into HEK293T cells followed by Western blotting revealed slight reduction of MORC2 protein quantity compared to wt vector. doi: 10.1093/brain/awv411, doi: 10.1093/brain/awv311; SCV006558552: Variants in MORC2 are associated to an axonal form of Charcot-Marie-Tooth neuropathy type 2Z (PMID: 26659848, 34059105), which corresponds to the clinical diagnosis of the proband. PMID: 30624633; SCV001786107: Published functional studies demonstrate a damaging, gain-of-function effect (Tchasovnikarova et al., 2017; Douse et al., 2018)
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr22-30941502-C-A is described in ClinVar as Pathogenic. ClinVar VariationId is 3897854.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.855
• PP5: Variant 22-30941503-G-A is Pathogenic according to our data. Variant chr22-30941503-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 218307.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MORC2	NM_001303256.3	MANE Select	c.754C>T	p.Arg252Trp	missense	Exon 9 of 26	NP_001290185.1	Q9Y6X9-1
	MORC2	NM_001303257.2		c.754C>T	p.Arg252Trp	missense	Exon 9 of 26	NP_001290186.1	Q9Y6X9
	MORC2	NM_014941.3		c.568C>T	p.Arg190Trp	missense	Exon 10 of 27	NP_055756.1	Q9Y6X9-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MORC2	ENST00000397641.8	TSL:5 MANE Select	c.754C>T	p.Arg252Trp	missense	Exon 9 of 26	ENSP00000380763.2	Q9Y6X9-1
	MORC2	ENST00000215862.8	TSL:1	c.568C>T	p.Arg190Trp	missense	Exon 10 of 27	ENSP00000215862.4	Q9Y6X9-2
	MORC2	ENST00000924805.1		c.754C>T	p.Arg252Trp	missense	Exon 9 of 26	ENSP00000594864.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
12	-	-	Charcot-Marie-Tooth disease axonal type 2Z (12)
3	-	-	not provided (3)
-	1	-	Charcot-Marie-Tooth disease (1)
1	-	-	Developmental delay, impaired growth, dysmorphic facies, and axonal neuropathy (1)
-	1	-	Distal spinal muscular atrophy (1)
1	-	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.82
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.23
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.32	T
Eigen	Uncertain	0.29
Eigen_PC	Uncertain	0.25
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.84	T
M_CAP	Uncertain	0.23	D
MetaRNN	Pathogenic	0.85	D
MetaSVM	Uncertain	0.046	D
MutationAssessor	Uncertain	2.3	M
PhyloP100		3.1
PrimateAI	Pathogenic	0.90	D
PROVEAN	Uncertain	-3.5	D
REVEL	Pathogenic	0.70
Sift	Benign	0.051	T
Sift4G	Benign	0.17	T
Polyphen		1.0	D
Vest4		0.91
MutPred		0.57		Loss of sheet (P = 0.0037)
MVP		0.76
MPC		2.1
ClinPred		0.97	D
GERP RS		2.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Varity_R		0.65
gMVP		0.89
Mutation Taster		=12/88	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs864309503; hg19: chr22-31337490; COSMIC: COSV53196061; COSMIC: COSV53196061;