chr19-42334083-C-G

Variant names:

• chr19-42334083-C-G
• rs765654107
• NM_001271938.2:c.428C>G

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001271938.2(MEGF8):​c.428C>G​(p.Pro143Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P143L) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MEGF8 NM_001271938.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.59
• Publications: 0 publications found

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

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.34786648).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MEGF8	NM_001271938.2	c.428C>G	p.Pro143Arg	missense_variant	Exon 3 of 42	ENST00000251268.11	NP_001258867.1
MEGF8	NM_001410.3	c.428C>G	p.Pro143Arg	missense_variant	Exon 3 of 41		NP_001401.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MEGF8	ENST00000251268.11	c.428C>G	p.Pro143Arg	missense_variant	Exon 3 of 42	5	NM_001271938.2	ENSP00000251268.5
MEGF8	ENST00000334370.8	c.428C>G	p.Pro143Arg	missense_variant	Exon 3 of 41	1		ENSP00000334219.4
MEGF8	ENST00000378073.5	c.-6658C>G		5_prime_UTR_variant	Exon 3 of 41	5		ENSP00000367313.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.50
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.59	.;D
Eigen	Benign	0.12
Eigen_PC	Benign	0.096
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.87	D;D
M_CAP	Uncertain	0.090	D
MetaRNN	Benign	0.35	T;T
MetaSVM	Benign	-0.92	T
MutationAssessor	Uncertain	2.2	M;M
PhyloP100		2.6
PrimateAI	Uncertain	0.53	T
PROVEAN	Pathogenic	-5.2	D;D
REVEL	Benign	0.14
Sift	Uncertain	0.024	D;D
Sift4G	Uncertain	0.0050	D;D
Polyphen		0.27	B;.
Vest4		0.54
MutPred		0.47		Gain of relative solvent accessibility (P = 0.1259);Gain of relative solvent accessibility (P = 0.1259);
MVP		0.082
MPC		0.79
ClinPred		0.97	D
GERP RS		3.8
Varity_R		0.26
gMVP		0.68
Mutation Taster		=46/54	disease causing

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

Other links and lift over

dbSNP: rs765654107; hg19: chr19-42838235;