rs62648096

Variant names:

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BS1BS2

The NM_001271938.2(MEGF8):c.5634C>T(p.Arg1878Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00716 in 1,612,282 control chromosomes in the GnomAD database, including 56 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0065 ( 6 hom., cov: 32)

Exomes 𝑓: 0.0072 ( 50 hom. )

Consequence

MEGF8
NM_001271938.2 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 0.239

Publications

4 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: Benign. The variant received -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.38).

BP6

Variant 19-42360920-C-T is Benign according to our data. Variant chr19-42360920-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 473336.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.239 with no splicing effect.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00647 (986/152362) while in subpopulation AMR AF = 0.00738 (113/15310). AF 95% confidence interval is 0.00668. There are 6 homozygotes in GnomAd4. There are 536 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MEGF8	NM_001271938.2 link	c.5634C>T	p.Arg1878Arg	synonymous_variant	Exon 32 of 42	ENST00000251268.11	NP_001258867.1	Q7Z7M0-1
MEGF8	NM_001410.3 link	c.5433C>T	p.Arg1811Arg	synonymous_variant	Exon 31 of 41		NP_001401.2	Q7Z7M0-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
MEGF8	ENST00000251268.11 link	c.5634C>T	p.Arg1878Arg	synonymous_variant	Exon 32 of 42	5	NM_001271938.2	ENSP00000251268.5	Q7Z7M0-1
MEGF8	ENST00000334370.8 link	c.5433C>T	p.Arg1811Arg	synonymous_variant	Exon 31 of 41	1		ENSP00000334219.4	Q7Z7M0-2
MEGF8	ENST00000378073.5 link	c.-1452C>T		5_prime_UTR_variant	Exon 32 of 41	5		ENSP00000367313.4	F5GZG7
MEGF8	ENST00000598762.1 link	c.-52C>T		upstream_gene_variant		3		ENSP00000471370.1	M0R0Q0

Frequencies

GnomAD3 genomes

AF:

0.00648

AC:

986

AN:

152244

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00169

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00739

Gnomad ASJ

AF:

0.0233

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00186

Gnomad FIN

AF:

0.0191

Gnomad MID

AF:

0.0158

Gnomad NFE

AF:

0.00720

Gnomad OTH

AF:

0.00669

GnomAD2 exomes

AF:

0.00794

AC:

1957

AN:

246608

AF XY:

0.00812

show subpopulations

Gnomad AFR exome

AF:

0.00119

Gnomad AMR exome

AF:

0.00546

Gnomad ASJ exome

AF:

0.0223

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.0165

Gnomad NFE exome

AF:

0.00952

Gnomad OTH exome

AF:

0.0106

GnomAD4 exome

AF:

0.00724

AC:

10566

AN:

1459920

Hom.:

Cov.:

AF XY:

0.00723

AC XY:

5247

AN XY:

726044

show subpopulations

African (AFR)

AF:

0.00129

AC:

AN:

33458

American (AMR)

AF:

0.00592

AC:

264

AN:

44602

Ashkenazi Jewish (ASJ)

AF:

0.0238

AC:

619

AN:

26056

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39674

South Asian (SAS)

AF:

0.00223

AC:

192

AN:

86094

European-Finnish (FIN)

AF:

0.0158

AC:

837

AN:

52936

Middle Eastern (MID)

AF:

0.0177

AC:

102

AN:

5754

European-Non Finnish (NFE)

AF:

0.00720

AC:

7999

AN:

1111036

Other (OTH)

AF:

0.00844

AC:

509

AN:

60310

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

Heterozygous variant carriers

604

1209

1813

2418

3022

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

270

540

810

1080

1350

<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:

0.00647

AC:

986

AN:

152362

Hom.:

Cov.:

AF XY:

0.00719

AC XY:

536

AN XY:

74500

show subpopulations

African (AFR)

AF:

0.00168

AC:

AN:

41588

American (AMR)

AF:

0.00738

AC:

113

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

0.0233

AC:

AN:

3472

East Asian (EAS)

AF:

0.000193

AC:

AN:

5186

South Asian (SAS)

AF:

0.00186

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.0191

AC:

203

AN:

10618

Middle Eastern (MID)

AF:

0.0170

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00720

AC:

490

AN:

68036

Other (OTH)

AF:

0.00662

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

102

153

204

255

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:

0.00825

Hom.:

Bravo

AF:

0.00557

Asia WGS

AF:

0.00318

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Mar 31, 2021

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

MEGF8: BP4, BP7, BS2 -

MEGF8-related Carpenter syndrome

Benign:1

Jan 28, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

MEGF8-related disorder

Benign:1

Jan 19, 2023

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.38

CADD

Benign

7.7

(source)

DANN

Benign

0.74

PhyloP100

0.24

PromoterAI

0.0035

Neutral

(source)

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over