chr19-42358892-C-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBP6BS1

The NM_001271938.2(MEGF8):c.5281C>G(p.Leu1761Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000583 in 1,611,558 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 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. L1761L) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00044 ( 1 hom., cov: 31)

Exomes 𝑓: 0.00060 ( 1 hom. )

Consequence

MEGF8
NM_001271938.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:2

Conservation

PhyloP100: -0.473

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: 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 -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.019727409).

BP6

Variant 19-42358892-C-G is Benign according to our data. Variant chr19-42358892-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 473334.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000441 (67/151960) while in subpopulation NFE AF = 0.000941 (64/67990). AF 95% confidence interval is 0.000756. There are 1 homozygotes in GnomAd4. There are 31 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.

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.5281C>G	p.Leu1761Val	missense	Exon 30 of 42	NP_001258867.1	Q7Z7M0-1
	MEGF8	NM_001410.3		c.5080C>G	p.Leu1694Val	missense	Exon 29 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.5281C>G	p.Leu1761Val	missense	Exon 30 of 42	ENSP00000251268.5	Q7Z7M0-1
MEGF8	ENST00000334370.8	TSL:1	c.5080C>G	p.Leu1694Val	missense	Exon 29 of 41	ENSP00000334219.4	Q7Z7M0-2
MEGF8	ENST00000378073.5	TSL:5	c.-1805C>G		5_prime_UTR_premature_start_codon_gain	Exon 30 of 41	ENSP00000367313.4	F5GZG7

Frequencies

GnomAD3 genomes

AF:

0.000441

AC:

AN:

151960

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000484

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000941

Gnomad OTH

AF:

0.000479

GnomAD2 exomes

AF:

0.000463

AC:

114

AN:

246420

AF XY:

0.000465

show subpopulations

Gnomad AFR exome

AF:

0.0000634

Gnomad AMR exome

AF:

0.000176

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000186

Gnomad NFE exome

AF:

0.000908

Gnomad OTH exome

AF:

0.000331

GnomAD4 exome

AF:

0.000597

AC:

872

AN:

1459598

Hom.:

Cov.:

AF XY:

0.000637

AC XY:

462

AN XY:

725806

show subpopulations

African (AFR)

AF:

0.0000598

AC:

AN:

33466

American (AMR)

AF:

0.000158

AC:

AN:

44376

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26044

East Asian (EAS)

AF:

0.00

AC:

AN:

39662

South Asian (SAS)

AF:

0.0000117

AC:

AN:

85548

European-Finnish (FIN)

AF:

0.000394

AC:

AN:

53344

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.000734

AC:

815

AN:

1111066

Other (OTH)

AF:

0.000431

AC:

AN:

60326

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

141

188

235

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

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

GnomAD4 genome

AF:

0.000441

AC:

AN:

151960

Hom.:

Cov.:

AF XY:

0.000418

AC XY:

AN XY:

74216

show subpopulations

African (AFR)

AF:

0.0000484

AC:

AN:

41334

American (AMR)

AF:

0.00

AC:

AN:

15256

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5178

South Asian (SAS)

AF:

0.00

AC:

AN:

4816

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10602

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000941

AC:

AN:

67990

Other (OTH)

AF:

0.000479

AC:

AN:

2088

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

Age Distribution

Genome Het

Genome Hom

Variant carriers

<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:

0.000539

Hom.:

Bravo

AF:

0.000393

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000698

AC:

ExAC

AF:

0.000577

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Inborn genetic diseases (1)

MEGF8-related Carpenter syndrome (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.085

BayesDel_addAF

Benign

-0.65

BayesDel_noAF

Benign

-0.73

CADD

Benign

0.10

(source)

DANN

Benign

0.25

DEOGEN2

Benign

0.070

Eigen

Benign

-1.6

Eigen_PC

Benign

-1.7

FATHMM_MKL

Benign

0.023

LIST_S2

Benign

0.53

M_CAP

Benign

0.011

MetaRNN

Benign

0.020

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.0

PhyloP100

-0.47

PrimateAI

Benign

0.31

PROVEAN

Benign

-0.30

REVEL

Benign

0.0010

Sift

Benign

0.17

Sift4G

Benign

0.15

Polyphen

0.0

Vest4

0.12

MVP

0.12

MPC

0.033

ClinPred

0.022

GERP RS

-5.1

Varity_R

0.034

gMVP

0.23

Mutation Taster

=98/2

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