rs1555936598

Variant names:

• chr22-30932688-G-GCCCTCCTGTTGTGTATCAA
• rs1555936598
• NM_001303256.3:c.2585_2603dupTTGATACACAACAGGAGGG

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PVS1

The NM_001303256.3(MORC2):​c.2585_2603dupTTGATACACAACAGGAGGG​(p.Gly869fs) variant causes a frameshift, stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. G868G) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 33)
• Consequence: MORC2 NM_001303256.3 frameshift, stop_gained
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.20
• 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-AS1 (HGNC:26662): (MORC2 antisense RNA 1)

ACMG classification

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

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.2585_2603dupTTGATACACAACAGGAGGG	p.Gly869fs	frameshift stop_gained	Exon 23 of 26	NP_001290185.1	Q9Y6X9-1
	MORC2	NM_001303257.2		c.2585_2603dupTTGATACACAACAGGAGGG	p.Gly869fs	frameshift stop_gained	Exon 23 of 26	NP_001290186.1	Q9Y6X9
	MORC2	NM_014941.3		c.2399_2417dupTTGATACACAACAGGAGGG	p.Gly807fs	frameshift stop_gained	Exon 24 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.2585_2603dupTTGATACACAACAGGAGGG	p.Gly869fs	frameshift stop_gained	Exon 23 of 26	ENSP00000380763.2	Q9Y6X9-1
	MORC2	ENST00000215862.8	TSL:1	c.2399_2417dupTTGATACACAACAGGAGGG	p.Gly807fs	frameshift stop_gained	Exon 24 of 27	ENSP00000215862.4	Q9Y6X9-2
	MORC2	ENST00000924805.1		c.2585_2603dupTTGATACACAACAGGAGGG	p.Gly869fs	frameshift stop_gained	Exon 23 of 26	ENSP00000594864.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.2

Splicing

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

Other links and lift over

dbSNP: rs1555936598; hg19: chr22-31328675;