rs147216997

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_001271938.2(MEGF8):c.7673C>T(p.Pro2558Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00752 in 1,599,210 control chromosomes in the GnomAD database, including 45 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. P2558P) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0062 ( 7 hom., cov: 32)

Exomes 𝑓: 0.0077 ( 38 hom. )

Consequence

MEGF8
NM_001271938.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:6

Conservation

PhyloP100: 0.302

Publications

5 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: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P, ClinGen
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: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0047466457).

BP6

Variant 19-42375910-C-T is Benign according to our data. Variant chr19-42375910-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 235520.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00615 (937/152302) while in subpopulation NFE AF = 0.01 (681/68012). AF 95% confidence interval is 0.00939. There are 7 homozygotes in GnomAd4. There are 412 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 7 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001271938.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MEGF8	NM_001271938.2	MANE Select	c.7673C>T	p.Pro2558Leu	missense	Exon 42 of 42	NP_001258867.1	Q7Z7M0-1
	MEGF8	NM_001410.3		c.7472C>T	p.Pro2491Leu	missense	Exon 41 of 41	NP_001401.2	Q7Z7M0-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MEGF8	ENST00000251268.11	TSL:5 MANE Select	c.7673C>T	p.Pro2558Leu	missense	Exon 42 of 42	ENSP00000251268.5	Q7Z7M0-1
MEGF8	ENST00000334370.8	TSL:1	c.7472C>T	p.Pro2491Leu	missense	Exon 41 of 41	ENSP00000334219.4	Q7Z7M0-2
MEGF8	ENST00000593647.1	TSL:1	c.*262C>T		3_prime_UTR	Exon 4 of 4	ENSP00000470620.1	M0QZL2

Frequencies

GnomAD3 genomes

AF:

0.00616

AC:

937

AN:

152184

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00166

Gnomad AMI

AF:

0.0110

Gnomad AMR

AF:

0.00386

Gnomad ASJ

AF:

0.00144

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00145

Gnomad FIN

AF:

0.00828

Gnomad MID

AF:

0.0190

Gnomad NFE

AF:

0.0100

Gnomad OTH

AF:

0.00574

GnomAD2 exomes

AF:

0.00576

AC:

1333

AN:

231274

AF XY:

0.00591

show subpopulations

Gnomad AFR exome

AF:

0.00120

Gnomad AMR exome

AF:

0.00299

Gnomad ASJ exome

AF:

0.00197

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00860

Gnomad NFE exome

AF:

0.00867

Gnomad OTH exome

AF:

0.00644

GnomAD4 exome

AF:

0.00766

AC:

11085

AN:

1446908

Hom.:

Cov.:

AF XY:

0.00751

AC XY:

5396

AN XY:

718180

show subpopulations

African (AFR)

AF:

0.00150

AC:

AN:

33230

American (AMR)

AF:

0.00290

AC:

126

AN:

43412

Ashkenazi Jewish (ASJ)

AF:

0.00206

AC:

AN:

25198

East Asian (EAS)

AF:

0.0000507

AC:

AN:

39484

South Asian (SAS)

AF:

0.00286

AC:

242

AN:

84578

European-Finnish (FIN)

AF:

0.00887

AC:

455

AN:

51272

Middle Eastern (MID)

AF:

0.0149

AC:

AN:

5704

European-Non Finnish (NFE)

AF:

0.00879

AC:

9704

AN:

1104368

Other (OTH)

AF:

0.00618

AC:

369

AN:

59662

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

Heterozygous variant carriers

722

1444

2166

2888

3610

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

354

708

1062

1416

1770

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00615

AC:

937

AN:

152302

Hom.:

Cov.:

AF XY:

0.00553

AC XY:

412

AN XY:

74462

show subpopulations

African (AFR)

AF:

0.00166

AC:

AN:

41582

American (AMR)

AF:

0.00385

AC:

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.00144

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5152

South Asian (SAS)

AF:

0.00145

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00828

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.0204

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0100

AC:

681

AN:

68012

Other (OTH)

AF:

0.00568

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

101

151

202

252

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00716

Hom.:

Bravo

AF:

0.00506

TwinsUK

AF:

0.00647

AC:

ALSPAC

AF:

0.00752

AC:

ESP6500AA

AF:

0.00208

AC:

ESP6500EA

AF:

0.00696

AC:

ExAC

AF:

0.00569

AC:

685

Asia WGS

AF:

0.00173

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (4)

Inborn genetic diseases (1)

MEGF8-related Carpenter syndrome (1)

MEGF8-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.097

BayesDel_addAF

Benign

-0.65

BayesDel_noAF

Benign

-0.70

CADD

Benign

5.2

(source)

DANN

Benign

0.43

DEOGEN2

Benign

0.096

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.11

LIST_S2

Benign

0.75

MetaRNN

Benign

0.0047

MetaSVM

Benign

-0.96

MutationAssessor

Benign

0.69

PhyloP100

0.30

PrimateAI

Uncertain

0.53

PROVEAN

Benign

-1.6

REVEL

Benign

0.043

Sift

Benign

0.38

Sift4G

Benign

0.083

Polyphen

0.0030

Vest4

0.17

MVP

0.043

MPC

0.55

ClinPred

0.0039

GERP RS

0.090

Varity_R

0.037

gMVP

0.37

Mutation Taster

=90/10

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over