rs748092969

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 1P and 10B. PP2BP4BP6BS1BS2

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).

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

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

PP2

Missense variant in the MORC2 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 25 curated pathogenic missense variants (we use a threshold of 10). The gene has 13 curated benign missense variants. Gene score misZ: 3.2251 (above the threshold of 3.09). Trascript score misZ: 4.4393 (above the threshold of 3.09). GenCC associations: The gene is linked to Leigh syndrome, Charcot-Marie-Tooth disease axonal type 2Z, developmental delay, impaired growth, dysmorphic facies, and axonal neuropathy.

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 id is 581920.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=2}.

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 male gnomad4 subpopulation. Median coverage is 28. This position pass quality control queck.

BS2

High AC in GnomAdExome4 at 14 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MORC2	NM_001303256.3 link	c.187A>T	p.Met63Leu	missense_variant	Exon 4 of 26	ENST00000397641.8	NP_001290185.1	Q9Y6X9-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
MORC2	ENST00000397641.8 link	c.187A>T	p.Met63Leu	missense_variant	Exon 4 of 26	5	NM_001303256.3	ENSP00000380763.2	Q9Y6X9-1
MORC2	ENST00000215862.8 link	c.1A>T	p.Met1?	initiator_codon_variant	Exon 5 of 27	1		ENSP00000215862.4	Q9Y6X9-2
MORC2	ENST00000476152.2 link	n.309A>T		non_coding_transcript_exon_variant	Exon 3 of 7	5

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

GnomAD3 exomes

AF:

0.0000478

AC:

AN:

251236

Hom.:

AF XY:

0.0000589

AC XY:

AN XY:

135814

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 SAS exome

AF:

0.0000327

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

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000567

Gnomad4 SAS exome

AF:

0.0000118

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000167

AC:

AN:

119554

Hom.:

Cov.:

AF XY:

0.0000365

AC XY:

AN XY:

54736

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000561

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000416

ExAC

AF:

0.0000659

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:1

Oct 26, 2020

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 30, 2021

Revvity Omics, Revvity

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Charcot-Marie-Tooth disease axonal type 2Z

Uncertain:1

Sep 19, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces methionine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 63 of the MORC2 protein (p.Met63Leu). This variant is present in population databases (rs748092969, gnomAD 0.06%). This variant has not been reported in the literature in individuals affected with MORC2-related conditions. ClinVar contains an entry for this variant (Variation ID: 581920). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt MORC2 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Pathogenic

0.17

BayesDel_noAF

Pathogenic

0.34

CADD

Uncertain

DANN

Benign

0.97

DEOGEN2

Benign

0.40

T;.

Eigen

Uncertain

0.44

Eigen_PC

Uncertain

0.54

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.88

D;D

M_CAP

Uncertain

0.14

MetaRNN

Benign

0.27

T;T

MetaSVM

Uncertain

0.68

MutationAssessor

Benign

-0.30

N;.

PROVEAN

Benign

-1.9

N;N

REVEL

Uncertain

0.53

Sift

Benign

0.47

T;T

Sift4G

Benign

0.28

T;T

Polyphen

0.93

P;.

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

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over