chr22-30950416-T-C

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PVS1_SupportingPM2

The NM_014941.3(MORC2):c.1A>G(p.Met1?) variant causes a start lost change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000784 in 1,275,590 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000084 ( 0 hom., cov: 28)

Exomes 𝑓: 7.8e-7 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

MORC2
NM_014941.3 start_lost

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.45

Publications

1 publications found

Variant links:

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 Gene-Disease associations (from GenCC):

Charcot-Marie-Tooth disease axonal type 2Z
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), ClinGen
developmental delay, impaired growth, dysmorphic facies, and axonal neuropathy
Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
Leigh syndrome
Inheritance: AD Classification: LIMITED Submitted by: ClinGen

MORC2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PVS1

Start lost variant, no pathogenic variants between lost start and next in-frame start position. Next in-frame start position is after 11 codons. Genomic position: 30950386. Lost 0.011 part of the original CDS.

PM2

Very rare variant in population databases, with high coverage;

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014941.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MORC2	NM_001303256.3	MANE Select	c.187A>G	p.Met63Val	missense	Exon 4 of 26	NP_001290185.1	Q9Y6X9-1
MORC2	NM_014941.3		c.1A>G	p.Met1?	start_lost	Exon 5 of 27	NP_055756.1	Q9Y6X9-2
MORC2	NM_001303257.2		c.187A>G	p.Met63Val	missense	Exon 4 of 26	NP_001290186.1	Q9Y6X9

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MORC2	ENST00000215862.8	TSL:1	c.1A>G	p.Met1?	start_lost	Exon 5 of 27	ENSP00000215862.4	Q9Y6X9-2
MORC2	ENST00000397641.8	TSL:5 MANE Select	c.187A>G	p.Met63Val	missense	Exon 4 of 26	ENSP00000380763.2	Q9Y6X9-1
MORC2	ENST00000924805.1		c.187A>G	p.Met63Val	missense	Exon 4 of 26	ENSP00000594864.1

Frequencies

GnomAD3 genomes

AF:

0.00000836

AC:

AN:

119554

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000324

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000796

AC:

AN:

251236

AF XY:

0.00000736

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

7.84e-7

AC:

AN:

1275590

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

632756

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

27984

American (AMR)

AF:

0.00

AC:

AN:

38906

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19200

East Asian (EAS)

AF:

0.00

AC:

AN:

22910

South Asian (SAS)

AF:

0.00

AC:

AN:

84594

European-Finnish (FIN)

AF:

0.00

AC:

AN:

38118

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4838

European-Non Finnish (NFE)

AF:

0.00000101

AC:

AN:

991158

Other (OTH)

AF:

0.00

AC:

AN:

47882

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.375

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00000836

AC:

AN:

119554

Hom.:

Cov.:

AF XY:

0.0000183

AC XY:

AN XY:

54736

show subpopulations

African (AFR)

AF:

0.0000324

AC:

AN:

30884

American (AMR)

AF:

0.00

AC:

AN:

7910

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3328

East Asian (EAS)

AF:

0.00

AC:

AN:

3566

South Asian (SAS)

AF:

0.00

AC:

AN:

3630

European-Finnish (FIN)

AF:

0.00

AC:

AN:

4628

Middle Eastern (MID)

AF:

0.00

AC:

AN:

114

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

63032

Other (OTH)

AF:

0.00

AC:

AN:

1586

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Developmental delay, impaired growth, dysmorphic facies, and axonal neuropathy (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Pathogenic

0.46

BayesDel_noAF

Pathogenic

0.44

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.47

Eigen

Uncertain

0.67

Eigen_PC

Pathogenic

0.69

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.93

M_CAP

Pathogenic

0.29

MetaRNN

Uncertain

0.68

MetaSVM

Pathogenic

0.86

MutationAssessor

Benign

1.2

PhyloP100

7.5

PROVEAN

Uncertain

-2.9

REVEL

Uncertain

0.63

Sift

Benign

0.077

Sift4G

Uncertain

0.016

Polyphen

0.98

Vest4

0.71

MutPred

0.49

Loss of catalytic residue at M63 (P = 0.0722)

MVP

0.97

ClinPred

0.69

GERP RS

5.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.62

gMVP

0.83

Mutation Taster

=6/194

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

Details are displayed if max score is > 0.2

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over