rs67357185

Variant names:

• chr22-30932538-CAT-C
• rs67357185
• NM_001303256.3:c.2747+5_2747+6delAT

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_001303256.3(MORC2):​c.2747+5_2747+6delAT variant causes a splice region, intron change. The variant allele was found at a frequency of 0.000571 in 1,613,960 control chromosomes in the GnomAD database, including 1 homozygotes. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0031 (1 hom., cov: 33)
  • Exomes 𝑓: 0.00031 (0 hom.)
• Consequence: MORC2 NM_001303256.3 splice_region, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 4.77
• 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: Benign. The variant received -16 ACMG points.

• BP6: Variant 22-30932538-CAT-C is Benign according to our data. Variant chr22-30932538-CAT-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 475587.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00309 (471/152244) while in subpopulation AFR AF = 0.0107 (443/41548). AF 95% confidence interval is 0.00984. There are 1 homozygotes in GnomAd4. There are 233 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 471 AD gene.

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.2747+5_2747+6delAT		splice_region intron	N/A	NP_001290185.1	Q9Y6X9-1
	MORC2	NM_001303257.2		c.2747+5_2747+6delAT		splice_region intron	N/A	NP_001290186.1	Q9Y6X9
	MORC2	NM_014941.3		c.2561+5_2561+6delAT		splice_region intron	N/A	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.2747+5_2747+6delAT		splice_region intron	N/A	ENSP00000380763.2	Q9Y6X9-1
	MORC2	ENST00000215862.8	TSL:1	c.2561+5_2561+6delAT		splice_region intron	N/A	ENSP00000215862.4	Q9Y6X9-2
	MORC2	ENST00000924805.1		c.2752_2753delAT	p.Met918fs	frameshift splice_region	Exon 23 of 26	ENSP00000594864.1

Frequencies

GnomAD3 genomes AF: 0.00306 AC: 466 AN: 152126 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.0106

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00124

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00287

GnomAD2 exomes AF: 0.000776 AC: 195 AN: 251242 AF XY: 0.000648

Gnomad AFR exome AF: 0.0104

Gnomad AMR exome AF: 0.000579

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000352

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000308 AC: 450 AN: 1461716 Hom.: 0 AF XY: 0.000282 AC XY: 205 AN XY: 727160

African (AFR) AF: 0.0106 AC: 355 AN: 33480

American (AMR) AF: 0.000626 AC: 28 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26120

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000348 AC: 3 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.000693 AC: 4 AN: 5768

European-Non Finnish (NFE) AF: 0.0000270 AC: 30 AN: 1111876

Other (OTH) AF: 0.000497 AC: 30 AN: 60388

GnomAD4 genome AF: 0.00309 AC: 471 AN: 152244 Hom.: 1 Cov.: 33 AF XY: 0.00313 AC XY: 233 AN XY: 74428

African (AFR) AF: 0.0107 AC: 443 AN: 41548

American (AMR) AF: 0.00124 AC: 19 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5168

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10608

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68026

Other (OTH) AF: 0.00284 AC: 6 AN: 2114

Alfa AF: 0.00178 Hom.: 0

Bravo AF: 0.00361

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	Charcot-Marie-Tooth disease axonal type 2Z (2)
-	-	1	Developmental delay, impaired growth, dysmorphic facies, and axonal neuropathy (1)
-	-	1	Inborn genetic diseases (1)
-	-	1	MORC2-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		4.8
Mutation Taster		=30/70	disease causing

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: rs67357185; hg19: chr22-31328525;