NM_001256545.2:c.2199C>T

Variant names:

• chr5-127438533-C-T
• rs35591368
• NM_001256545.2:c.2199C>T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_001256545.2(MEGF10):​c.2199C>T​(p.Cys733Cys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0308 in 1,614,016 control chromosomes in the GnomAD database, including 854 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.026 (49 hom., cov: 32)
  • Exomes 𝑓: 0.031 (805 hom.)
• Consequence: MEGF10 NM_001256545.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.287
• Publications: 7 publications found

Genes affected

MEGF10 (HGNC:29634): (multiple EGF like domains 10) This gene encodes a member of the multiple epidermal growth factor-like domains protein family. The encoded protein plays a role in cell adhesion, motility and proliferation, and is a critical mediator of apoptotic cell phagocytosis as well as amyloid-beta peptide uptake in the brain. Expression of this gene may be associated with schizophrenia, and mutations in this gene are a cause of early-onset myopathy, areflexia, respiratory distress, and dysphagia (EMARDD) as well as congenital myopathy with minicores. Alternatively spliced transcript variants have been observed for this gene. [provided by RefSeq, Apr 2012]

MEGF10 Gene-Disease associations (from GenCC):

• MEGF10-related myopathy

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, G2P, Labcorp Genetics (formerly Invitae), ClinGen

ACMG classification

Our verdict: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.43).
• BP6: Variant 5-127438533-C-T is Benign according to our data. Variant chr5-127438533-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 262072.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.287 with no splicing effect.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.026 (3963/152294) while in subpopulation EAS AF = 0.045 (233/5180). AF 95% confidence interval is 0.0402. There are 49 homozygotes in GnomAd4. There are 1829 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 49 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MEGF10	NM_001256545.2	c.2199C>T	p.Cys733Cys	synonymous_variant	Exon 17 of 25	ENST00000503335.7	NP_001243474.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MEGF10	ENST00000503335.7	c.2199C>T	p.Cys733Cys	synonymous_variant	Exon 17 of 25	1	NM_001256545.2	ENSP00000423354.2
MEGF10	ENST00000274473.6	c.2199C>T	p.Cys733Cys	synonymous_variant	Exon 18 of 26	1		ENSP00000274473.6
MEGF10	ENST00000506709.1	n.440C>T		non_coding_transcript_exon_variant	Exon 4 of 5	3

Frequencies

GnomAD3 genomes AF: 0.0260 AC: 3963 AN: 152176 Hom.: 49 Cov.: 32

Gnomad AFR AF: 0.0188

Gnomad AMI AF: 0.00548

Gnomad AMR AF: 0.0254

Gnomad ASJ AF: 0.0153

Gnomad EAS AF: 0.0449

Gnomad SAS AF: 0.0129

Gnomad FIN AF: 0.0190

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.0320

Gnomad OTH AF: 0.0278

GnomAD2 exomes AF: 0.0261 AC: 6501 AN: 249522 AF XY: 0.0259

Gnomad AFR exome AF: 0.0185

Gnomad AMR exome AF: 0.0198

Gnomad ASJ exome AF: 0.0189

Gnomad EAS exome AF: 0.0449

Gnomad FIN exome AF: 0.0207

Gnomad NFE exome AF: 0.0311

Gnomad OTH exome AF: 0.0260

GnomAD4 exome AF: 0.0312 AC: 45678 AN: 1461722 Hom.: 805 Cov.: 31 AF XY: 0.0307 AC XY: 22307 AN XY: 727168

African (AFR) AF: 0.0167 AC: 558 AN: 33480

American (AMR) AF: 0.0198 AC: 887 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0155 AC: 404 AN: 26134

East Asian (EAS) AF: 0.0372 AC: 1478 AN: 39696

South Asian (SAS) AF: 0.0134 AC: 1159 AN: 86258

European-Finnish (FIN) AF: 0.0224 AC: 1198 AN: 53406

Middle Eastern (MID) AF: 0.0280 AC: 161 AN: 5754

European-Non Finnish (NFE) AF: 0.0340 AC: 37797 AN: 1111882

Other (OTH) AF: 0.0337 AC: 2036 AN: 60390

GnomAD4 genome AF: 0.0260 AC: 3963 AN: 152294 Hom.: 49 Cov.: 32 AF XY: 0.0246 AC XY: 1829 AN XY: 74458

African (AFR) AF: 0.0187 AC: 779 AN: 41560

American (AMR) AF: 0.0253 AC: 387 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0153 AC: 53 AN: 3470

East Asian (EAS) AF: 0.0450 AC: 233 AN: 5180

South Asian (SAS) AF: 0.0129 AC: 62 AN: 4818

European-Finnish (FIN) AF: 0.0190 AC: 202 AN: 10612

Middle Eastern (MID) AF: 0.0306 AC: 9 AN: 294

European-Non Finnish (NFE) AF: 0.0320 AC: 2176 AN: 68036

Other (OTH) AF: 0.0270 AC: 57 AN: 2112

Alfa AF: 0.0276 Hom.: 58

Bravo AF: 0.0268

Asia WGS AF: 0.0260 AC: 91 AN: 3478

EpiCase AF: 0.0310

EpiControl AF: 0.0289

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Jan 28, 2016

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

MEGF10-related myopathy Benign:2

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.43
CADD	Benign	4.9
DANN	Benign	0.48
PhyloP100		0.29
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs35591368; hg19: chr5-126774225; COSMIC: COSV108037271;