chr22-30935025-G-A

Position:

chr22-30935025-G-A

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 1P and 7B. PP2BP4_ModerateBS1_SupportingBS2

The NM_001303256.3(MORC2):c.1949C>T(p.Thr650Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000155 in 1,613,982 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 31)

Exomes 𝑓: 0.00017 ( 0 hom. )

Consequence

MORC2
NM_001303256.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 2.14

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 Likely_benign. Variant got -6 ACMG points.

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), MORC2. . Gene score misZ: 3.2251 (greater than the threshold 3.09). Trascript score misZ: 4.4393 (greater than threshold 3.09). The gene has 25 curated pathogenic missense variants (we use a threshold of 10). The gene has 13 curated benign missense variants. GenCC has associacion of the gene with 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=0.07258645).

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0000329 (5/152110) while in subpopulation AFR AF= 0.0000483 (2/41426). AF 95% confidence interval is 0.0000117. There are 0 homozygotes in gnomad4. There are 3 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High AC in GnomAd4 at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MORC2	NM_001303256.3 link	c.1949C>T	p.Thr650Ile	missense_variant	19/26	ENST00000397641.8	NP_001290185.1	Q9Y6X9-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MORC2	ENST00000397641.8 link	c.1949C>T	p.Thr650Ile	missense_variant	19/26	5	NM_001303256.3	ENSP00000380763.2		Q9Y6X9-1

Frequencies

GnomAD3 genomes

AF:

0.0000329

AC:

AN:

152110

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

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:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000279

AC:

AN:

251030

Hom.:

AF XY:

0.0000516

AC XY:

AN XY:

135742

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 SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000617

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000168

AC:

245

AN:

1461872

Hom.:

Cov.:

AF XY:

0.000184

AC XY:

134

AN XY:

727232

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000217

Gnomad4 OTH exome

AF:

0.0000662

GnomAD4 genome

AF:

0.0000329

AC:

AN:

152110

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74302

show subpopulations

Gnomad4 AFR

AF:

0.0000483

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000579

Hom.:

Bravo

AF:

0.0000264

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000165

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.000119

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Charcot-Marie-Tooth disease axonal type 2Z

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 17, 2023

This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 650 of the MORC2 protein (p.Thr650Ile). This variant is present in population databases (rs371710965, gnomAD 0.006%). 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: 542291). 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 not expected to disrupt MORC2 protein function with a negative predictive value of 95%. 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. -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 24, 2021

The p.T650I variant (also known as c.1949C>T), located in coding exon 19 of the MORC2 gene, results from a C to T substitution at nucleotide position 1949. The threonine at codon 650 is replaced by isoleucine, an amino acid with similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.075

BayesDel_addAF

Benign

-0.46

BayesDel_noAF

Benign

-0.72

CADD

Benign

DANN

Benign

0.94

DEOGEN2

Benign

0.049

T;.

Eigen

Benign

-0.86

Eigen_PC

Benign

-0.81

FATHMM_MKL

Uncertain

0.87

LIST_S2

Benign

0.32

T;T

M_CAP

Benign

0.0052

MetaRNN

Benign

0.073

T;T

MetaSVM

Benign

-0.96

MutationAssessor

Benign

0.34

N;.

PrimateAI

Benign

0.33

PROVEAN

Benign

-1.2

N;N

REVEL

Benign

0.048

Sift

Benign

0.21

T;T

Sift4G

Benign

0.28

T;T

Polyphen

0.0

B;.

Vest4

0.097

MVP

0.093

MPC

0.16

ClinPred

0.026

GERP RS

1.3

Varity_R

0.016

gMVP

0.21

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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