Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4BP6BS1BS2

The NM_001303256.3(MORC2):c.187A>T(p.Met63Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000115 in 1,395,144 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M63V) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000017 ( 0 hom., cov: 28)

Exomes 𝑓: 0.000011 ( 0 hom. )

Consequence

MORC2
NM_001303256.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B: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: ClinGen, Orphanet, Labcorp Genetics (formerly Invitae)
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: Benign. The variant received -10 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.3911212).

BP6

Variant 22-30950416-T-A is Benign according to our data. Variant chr22-30950416-T-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 581920.

BS1

Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.0000167 (2/119554) while in subpopulation EAS AF = 0.000561 (2/3566). AF 95% confidence interval is 0.0000987. There are 0 homozygotes in GnomAd4. There are 2 alleles in the male GnomAd4 subpopulation. Median coverage is 28. This position passed quality control check.

BS2

High AC in GnomAdExome4 at 14 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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
MORC2	NM_001303256.3	MANE Select	c.187A>T	p.Met63Leu	missense	Exon 4 of 26	NP_001290185.1
MORC2	NM_001303257.2		c.187A>T	p.Met63Leu	missense	Exon 4 of 26	NP_001290186.1
MORC2	NM_014941.3		c.1A>T	p.Met1?	initiator_codon	Exon 5 of 27	NP_055756.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
MORC2	ENST00000397641.8	TSL:5 MANE Select	c.187A>T	p.Met63Leu	missense	Exon 4 of 26	ENSP00000380763.2
MORC2	ENST00000215862.8	TSL:1	c.1A>T	p.Met1?	initiator_codon	Exon 5 of 27	ENSP00000215862.4
MORC2	ENST00000476152.2	TSL:5	n.309A>T		non_coding_transcript_exon	Exon 3 of 7

Frequencies

GnomAD3 genomes

AF:

0.0000167

AC:

AN:

119554

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000561

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:

0.0000478

AC:

AN:

251236

AF XY:

0.0000589

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000598

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000110

AC:

AN:

1275590

Hom.:

Cov.:

AF XY:

0.0000142

AC XY:

AN XY:

632756

show subpopulations

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:

0.000567

AC:

AN:

22910

South Asian (SAS)

AF:

0.0000118

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:

0.00

AC:

AN:

991158

Other (OTH)

AF:

0.00

AC:

AN:

47882

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000167

AC:

AN:

119554

Hom.:

Cov.:

AF XY:

0.0000365

AC XY:

AN XY:

54736

show subpopulations

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

African (AFR)

AF:

0.00

AC:

AN:

30884

American (AMR)

AF:

0.00

AC:

AN:

7910

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3328

East Asian (EAS)

AF:

0.000561

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

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.00000000770867), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.400

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000416

ExAC

AF:

0.0000659

AC:

ClinVar

ClinVar submissions as Germline

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Charcot-Marie-Tooth disease axonal type 2Z (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Pathogenic

0.17

BayesDel_noAF

Pathogenic

0.34

CADD

Uncertain

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.40

Eigen

Uncertain

0.44

Eigen_PC

Uncertain

0.54

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.88

M_CAP

Uncertain

0.14

MetaRNN

Benign

0.27

MetaSVM

Uncertain

0.68

MutationAssessor

Benign

-0.30

PhyloP100

7.5

PROVEAN

Benign

-1.9

REVEL

Uncertain

0.53

Sift

Benign

0.47

Sift4G

Benign

0.28

Polyphen

0.93

Vest4

0.61

MutPred

0.48

Loss of catalytic residue at M63 (P = 0.0047)

MVP

0.91

ClinPred

0.22

GERP RS

5.7

Varity_R

0.60

gMVP

0.79

Mutation Taster

=6/194

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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.

rs748092969

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over