22-30936507-G-A

Variant names:

• chr22-30936507-G-A
• rs5997814
• NM_001303256.3:c.1737+4C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The ENST00000397641.8(MORC2):​c.1737+4C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00072 in 1,613,984 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0039 (2 hom., cov: 32)
  • Exomes 𝑓: 0.00039 (3 hom.)
• Consequence: MORC2 ENST00000397641.8 splice_region, intron
• Scores: Splicing: ADA: 0.00007763
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -1.10
• Publications: 1 publications found

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

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.73).
• BP6: Variant 22-30936507-G-A is Benign according to our data. Variant chr22-30936507-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 475575.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00386 (587/152250) while in subpopulation AFR AF = 0.0135 (562/41546). AF 95% confidence interval is 0.0126. There are 2 homozygotes in GnomAd4. There are 286 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 587 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000397641.8. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MORC2	NM_001303256.3	MANE Select	c.1737+4C>T		splice_region intron	N/A	NP_001290185.1
	MORC2	NM_001303257.2		c.1737+4C>T		splice_region intron	N/A	NP_001290186.1
	MORC2	NM_014941.3		c.1551+4C>T		splice_region intron	N/A	NP_055756.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MORC2	ENST00000397641.8	TSL:5 MANE Select	c.1737+4C>T		splice_region intron	N/A	ENSP00000380763.2
	MORC2	ENST00000215862.8	TSL:1	c.1551+4C>T		splice_region intron	N/A	ENSP00000215862.4
	MORC2	ENST00000674576.1		n.3183+4C>T		splice_region intron	N/A

Frequencies

GnomAD3 genomes AF: 0.00381 AC: 580 AN: 152132 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.0134

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00105

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00287

GnomAD2 exomes AF: 0.00105 AC: 264 AN: 251254 AF XY: 0.000817

Gnomad AFR exome AF: 0.0143

Gnomad AMR exome AF: 0.000434

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000217

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000440

Gnomad OTH exome AF: 0.000815

GnomAD4 exome AF: 0.000393 AC: 575 AN: 1461734 Hom.: 3 Cov.: 31 AF XY: 0.000359 AC XY: 261 AN XY: 727164

African (AFR) AF: 0.0131 AC: 437 AN: 33476

American (AMR) AF: 0.000626 AC: 28 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26124

East Asian (EAS) AF: 0.000302 AC: 12 AN: 39700

South Asian (SAS) AF: 0.0000696 AC: 6 AN: 86238

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53392

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5768

European-Non Finnish (NFE) AF: 0.0000450 AC: 50 AN: 1111926

Other (OTH) AF: 0.000662 AC: 40 AN: 60394

GnomAD4 genome AF: 0.00386 AC: 587 AN: 152250 Hom.: 2 Cov.: 32 AF XY: 0.00384 AC XY: 286 AN XY: 74432

African (AFR) AF: 0.0135 AC: 562 AN: 41546

American (AMR) AF: 0.00105 AC: 16 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10606

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68024

Other (OTH) AF: 0.00284 AC: 6 AN: 2116

Alfa AF: 0.00146 Hom.: 3

Bravo AF: 0.00450

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	Charcot-Marie-Tooth disease axonal type 2Z (2)
-	-	1	Developmental delay, impaired growth, dysmorphic facies, and axonal neuropathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.73
CADD	Benign	0.35
DANN	Benign	0.82
PhyloP100		-1.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000078
dbscSNV1_RF	Benign	0.0
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

Other links and lift over

dbSNP: rs5997814; hg19: chr22-31332494;