NM_001303256.3:c.707A>C

Variant names:

• chr22-30941550-T-G
• rs886037934
• NM_001303256.3:c.707A>C

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2 PM5 PP2 PP5_Moderate

The NM_001303256.3(MORC2):​c.707A>C​(p.Glu236Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E236G) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MORC2 NM_001303256.3 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 7.67

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr22-30941550-T-C is described in Lovd as [Pathogenic].
• 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.
• PP5: Variant 22-30941550-T-G is Pathogenic according to our data. Variant chr22-30941550-T-G is described in ClinVar as [Pathogenic]. Clinvar id is 871542.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MORC2	NM_001303256.3	c.707A>C	p.Glu236Ala	missense_variant	Exon 9 of 26	ENST00000397641.8	NP_001290185.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MORC2	ENST00000397641.8	c.707A>C	p.Glu236Ala	missense_variant	Exon 9 of 26	5	NM_001303256.3	ENSP00000380763.2
MORC2	ENST00000215862.8	c.521A>C	p.Glu174Ala	missense_variant	Exon 10 of 27	1		ENSP00000215862.4
MORC2	ENST00000469915.1	n.261A>C		non_coding_transcript_exon_variant	Exon 3 of 6	3
MORC2	ENST00000675601.1	n.549A>C		non_coding_transcript_exon_variant	Exon 5 of 22

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Sep 01, 2017

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.89
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.030
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.28	T;.
Eigen	Uncertain	0.63
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D;D
M_CAP	Benign	0.032	D
MetaRNN	Uncertain	0.71	D;D
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.8	M;.
PrimateAI	Pathogenic	0.80	T
PROVEAN	Pathogenic	-5.0	D;D
REVEL	Uncertain	0.47
Sift	Benign	0.034	D;D
Sift4G	Uncertain	0.052	T;T
Polyphen		1.0	D;.
Vest4		0.87
MutPred		0.29		Loss of helix (P = 0.0138);.;
MVP		0.51
MPC		2.1
ClinPred		0.99	D
GERP RS		5.6
Varity_R		0.77
gMVP		0.83

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

LitVar

Other links and lift over

dbSNP: rs886037934; hg19: chr22-31337537;