22-30932643-G-A

Variant names:

• chr22-30932643-G-A
• rs189421529
• NM_001303256.3:c.2649C>T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Moderate BP6_Moderate BP7 BS1 BS2

The ENST00000397641.8(MORC2):​c.2649C>T​(p.Val883Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000258 in 1,614,144 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Synonymous variant affecting the same amino acid position (i.e. V883V) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00034 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00025 (1 hom.)
• Consequence: MORC2 ENST00000397641.8 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.366
• Publications: 5 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.046).
• BP6: Variant 22-30932643-G-A is Benign according to our data. Variant chr22-30932643-G-A is described in ClinVar as Benign. ClinVar VariationId is 475584.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=0.366 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000342 (52/152266) while in subpopulation SAS AF = 0.00269 (13/4832). AF 95% confidence interval is 0.00159. There are 0 homozygotes in GnomAd4. There are 31 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 52 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000397641.8. 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.2649C>T	p.Val883Val	synonymous	Exon 23 of 26	NP_001290185.1
	MORC2	NM_001303257.2		c.2649C>T	p.Val883Val	synonymous	Exon 23 of 26	NP_001290186.1
	MORC2	NM_014941.3		c.2463C>T	p.Val821Val	synonymous	Exon 24 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.2649C>T	p.Val883Val	synonymous	Exon 23 of 26	ENSP00000380763.2
	MORC2	ENST00000215862.8	TSL:1	c.2463C>T	p.Val821Val	synonymous	Exon 24 of 27	ENSP00000215862.4
	MORC2	ENST00000445980.5	TSL:5	c.132C>T	p.Val44Val	synonymous	Exon 2 of 5	ENSP00000402602.1

Frequencies

GnomAD3 genomes AF: 0.000342 AC: 52 AN: 152148 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000314

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00193

Gnomad SAS AF: 0.00269

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000191

Gnomad OTH AF: 0.000479

GnomAD2 exomes AF: 0.000481 AC: 121 AN: 251356 AF XY: 0.000537

Gnomad AFR exome AF: 0.000370

Gnomad AMR exome AF: 0.0000868

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00174

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000220

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000250 AC: 365 AN: 1461878 Hom.: 1 Cov.: 31 AF XY: 0.000305 AC XY: 222 AN XY: 727244

African (AFR) AF: 0.000358 AC: 12 AN: 33480

American (AMR) AF: 0.000112 AC: 5 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.000579 AC: 23 AN: 39700

South Asian (SAS) AF: 0.00166 AC: 143 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53408

Middle Eastern (MID) AF: 0.00416 AC: 24 AN: 5768

European-Non Finnish (NFE) AF: 0.000125 AC: 139 AN: 1112008

Other (OTH) AF: 0.000315 AC: 19 AN: 60396

GnomAD4 genome AF: 0.000342 AC: 52 AN: 152266 Hom.: 0 Cov.: 33 AF XY: 0.000416 AC XY: 31 AN XY: 74450

African (AFR) AF: 0.000313 AC: 13 AN: 41536

American (AMR) AF: 0.0000653 AC: 1 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00194 AC: 10 AN: 5166

South Asian (SAS) AF: 0.00269 AC: 13 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000191 AC: 13 AN: 68022

Other (OTH) AF: 0.000474 AC: 1 AN: 2110

Alfa AF: 0.0000994 Hom.: 0

Bravo AF: 0.000287

Asia WGS AF: 0.00231 AC: 8 AN: 3478

EpiCase AF: 0.000600

EpiControl AF: 0.000474

ClinVar

ClinVar submissions as Germline

Significance: Benign

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
BayesDel_noAF	Benign	-0.78
CADD	Benign	4.8
DANN	Benign	0.78
PhyloP100		0.37
PromoterAI		0.019	Neutral
Mutation Taster		=100/0	polymorphism

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: rs189421529; hg19: chr22-31328630; COSMIC: COSV99310261; COSMIC: COSV99310261;