Variant 19-42333607-C-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001271938.2(MEGF8):c.190C>G(p.Pro64Ala) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000342 in 1,461,150 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000034 ( 0 hom. )

Consequence

MEGF8
NM_001271938.2 missense, splice_region

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.02

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 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MEGF8	NM_001271938.2 linkuse as main transcript	c.190C>G	p.Pro64Ala	missense_variant, splice_region_variant	2/42	ENST00000251268.11
MEGF8	NM_001410.3 linkuse as main transcript	c.190C>G	p.Pro64Ala	missense_variant, splice_region_variant	2/41

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MEGF8	ENST00000251268.11 linkuse as main transcript	c.190C>G	p.Pro64Ala	missense_variant, splice_region_variant	2/42	5	NM_001271938.2	A2	Q7Z7M0-1
MEGF8	ENST00000334370.8 linkuse as main transcript	c.190C>G	p.Pro64Ala	missense_variant, splice_region_variant	2/41	1		P2	Q7Z7M0-2
MEGF8	ENST00000378073.5 linkuse as main transcript	c.-6896C>G		splice_region_variant, 5_prime_UTR_variant	2/41	5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000201

AC:

AN:

248594

Hom.:

AF XY:

0.0000148

AC XY:

AN XY:

134856

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000145

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS 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:

0.00000342

AC:

AN:

1461150

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

726840

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000112

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000756

ExAC

AF:

0.00000827

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 09, 2023

The c.190C>G (p.P64A) alteration is located in exon 2 (coding exon 2) of the MEGF8 gene. This alteration results from a C to G substitution at nucleotide position 190, causing the proline (P) at amino acid position 64 to be replaced by an alanine (A). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Benign

-0.22

BayesDel_noAF

Benign

-0.30

Cadd

Uncertain

Dann

Uncertain

0.99

Eigen

Uncertain

0.66

Eigen_PC

Pathogenic

0.67

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.91

D;D

M_CAP

Uncertain

0.14

MetaRNN

Uncertain

0.47

T;T

MetaSVM

Benign

-0.46

MutationAssessor

Benign

1.3

L;L

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.55

PROVEAN

Uncertain

-2.8

D;D

REVEL

Uncertain

0.34

Sift

Benign

0.27

T;T

Sift4G

Pathogenic

0.0

D;D

Polyphen

1.0

D;.

Vest4

0.49

MutPred

0.60

Loss of glycosylation at P64 (P = 0.0754);Loss of glycosylation at P64 (P = 0.0754);

MVP

0.50

MPC

1.2

ClinPred

0.84

GERP RS

5.3

Varity_R

0.066

gMVP

0.47

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over