NM_001271938.2:c.172G>A

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001271938.2(MEGF8):c.172G>A(p.Glu58Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000355 in 1,409,384 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000035 ( 0 hom. )

Consequence

MEGF8
NM_001271938.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 8.96

Publications

2 publications found

Variant links:

Genes affected

MEGF8 (HGNC:3233): (multiple EGF like domains 8) The protein encoded by this gene is a single-pass type I membrane protein of unknown function that contains several EGF-like domains, Kelch repeats, and PSI domains. Defects in this gene are a cause of Carpenter syndrome 2. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Dec 2012]

MEGF8 Gene-Disease associations (from GenCC):

MEGF8-related Carpenter syndrome
Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: PanelApp Australia, G2P, Ambry Genetics, ClinGen, Labcorp Genetics (formerly Invitae)
Carpenter syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

MEGF8 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MEGF8	NM_001271938.2 link	c.172G>A	p.Glu58Lys	missense_variant	Exon 1 of 42	ENST00000251268.11	NP_001258867.1	Q7Z7M0-1
MEGF8	NM_001410.3 link	c.172G>A	p.Glu58Lys	missense_variant	Exon 1 of 41		NP_001401.2	Q7Z7M0-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
MEGF8	ENST00000251268.11 link	c.172G>A	p.Glu58Lys	missense_variant	Exon 1 of 42	5	NM_001271938.2	ENSP00000251268.5	Q7Z7M0-1
MEGF8	ENST00000334370.8 link	c.172G>A	p.Glu58Lys	missense_variant	Exon 1 of 41	1		ENSP00000334219.4	Q7Z7M0-2
MEGF8	ENST00000378073.5 link	c.-6914G>A		5_prime_UTR_variant	Exon 1 of 41	5		ENSP00000367313.4	F5GZG7

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.0000225

AC:

AN:

177456

AF XY:

0.0000101

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000189

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000355

AC:

AN:

1409384

Hom.:

Cov.:

AF XY:

0.00000286

AC XY:

AN XY:

699778

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30222

American (AMR)

AF:

0.000118

AC:

AN:

33784

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24716

East Asian (EAS)

AF:

0.0000283

AC:

AN:

35282

South Asian (SAS)

AF:

0.00

AC:

AN:

78584

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51854

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5660

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1090980

Other (OTH)

AF:

0.00

AC:

AN:

58302

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000756

ExAC

AF:

0.0000166

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

MEGF8-related Carpenter syndrome

Uncertain:1

Apr 19, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals affected with MEGF8-related conditions. This variant is present in population databases (rs778995883, gnomAD 0.02%). This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 58 of the MEGF8 protein (p.Glu58Lys). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.97

BayesDel_addAF

Benign

-0.15

BayesDel_noAF

Benign

-0.18

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.33

.;T

Eigen

Pathogenic

0.86

Eigen_PC

Pathogenic

0.85

FATHMM_MKL

Uncertain

0.92

LIST_S2

Uncertain

0.95

D;D

M_CAP

Uncertain

0.095

MetaRNN

Uncertain

0.44

T;T

MetaSVM

Benign

-0.33

MutationAssessor

Uncertain

2.1

M;M

PhyloP100

9.0

PrimateAI

Uncertain

0.75

PROVEAN

Uncertain

-2.8

D;D

REVEL

Uncertain

0.36

Sift

Benign

0.031

D;D

Sift4G

Pathogenic

0.0

D;D

Polyphen

1.0

D;.

Vest4

0.47

MutPred

0.60

Gain of methylation at E58 (P = 0.0088);Gain of methylation at E58 (P = 0.0088);

MVP

0.19

MPC

1.3

ClinPred

0.76

GERP RS

5.6

Varity_R

0.38

gMVP

0.68

Mutation Taster

=37/63

disease causing

(source)

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

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NM_001271938.2:c.172G>A

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over