chr22-30935292-G-A

Position:

• chr22-30935292-G-A

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_001303256.3(MORC2):​c.1768C>T​(p.Leu590=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00139 in 1,613,832 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00075 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0015 (3 hom.)
• Consequence: MORC2 NM_001303256.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 2.18

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 Benign. Variant got -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.44).
• BP6: Variant 22-30935292-G-A is Benign according to our data. Variant chr22-30935292-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 475576.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-30935292-G-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=2.18 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000749 (114/152116) while in subpopulation NFE AF= 0.00137 (93/68020). AF 95% confidence interval is 0.00114. There are 0 homozygotes in gnomad4. There are 47 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 114 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MORC2	NM_001303256.3	c.1768C>T	p.Leu590=	synonymous_variant	18/26	ENST00000397641.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MORC2	ENST00000397641.8	c.1768C>T	p.Leu590=	synonymous_variant	18/26	5	NM_001303256.3	P1

Frequencies

GnomAD3 genomes AF: 0.000749 AC: 114 AN: 152116 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000193

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000524

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00137

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.000614 AC: 154 AN: 250994 Hom.: 0 AF XY: 0.000649 AC XY: 88 AN XY: 135640

Gnomad AFR exome AF: 0.000371

Gnomad AMR exome AF: 0.000319

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000164

Gnomad FIN exome AF: 0.0000925

Gnomad NFE exome AF: 0.00111

Gnomad OTH exome AF: 0.000653

GnomAD4 exome AF: 0.00145 AC: 2126 AN: 1461716 Hom.: 3 Cov.: 31 AF XY: 0.00138 AC XY: 1003 AN XY: 727128

Gnomad4 AFR exome AF: 0.000209

Gnomad4 AMR exome AF: 0.000403

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000232

Gnomad4 FIN exome AF: 0.000262

Gnomad4 NFE exome AF: 0.00180

Gnomad4 OTH exome AF: 0.00114

GnomAD4 genome AF: 0.000749 AC: 114 AN: 152116 Hom.: 0 Cov.: 31 AF XY: 0.000632 AC XY: 47 AN XY: 74312

Gnomad4 AFR AF: 0.000193

Gnomad4 AMR AF: 0.000524

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.000188

Gnomad4 NFE AF: 0.00137

Gnomad4 OTH AF: 0.000479

Alfa AF: 0.00111 Hom.: 0

Bravo AF: 0.000733

EpiCase AF: 0.00131

EpiControl AF: 0.00119

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Charcot-Marie-Tooth disease axonal type 2Z Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Mar 15, 2022	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 09, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	MORC2: BP4, BP7, BS1 -

MORC2-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 30, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Developmental delay, impaired growth, dysmorphic facies, and axonal neuropathy Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Mar 15, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.44
CADD	Benign	12
DANN	Benign	0.78
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs146972491; hg19: chr22-31331279;