chr19-42336021-G-C

Position:

• chr19-42336021-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001271938.2(MEGF8):​c.919G>C​(p.Val307Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 33)
• Consequence: MEGF8 NM_001271938.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.10

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2026813).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MEGF8	NM_001271938.2	c.919G>C	p.Val307Leu	missense_variant	6/42	ENST00000251268.11	NP_001258867.1
MEGF8	NM_001410.3	c.919G>C	p.Val307Leu	missense_variant	6/41		NP_001401.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MEGF8	ENST00000251268.11	c.919G>C	p.Val307Leu	missense_variant	6/42	5	NM_001271938.2	ENSP00000251268	A2
MEGF8	ENST00000334370.8	c.919G>C	p.Val307Leu	missense_variant	6/41	1		ENSP00000334219	P2
MEGF8	ENST00000378073.5	c.-6167G>C		5_prime_UTR_variant	6/41	5		ENSP00000367313

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	17
DANN	Benign	0.21
DEOGEN2	Benign	0.054	.;T
Eigen	Benign	-0.17
Eigen_PC	Benign	-0.11
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.84	T;T
M_CAP	Benign	0.033	D
MetaRNN	Benign	0.20	T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	0.080	N;N
MutationTaster	Benign	0.95	D;N
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	0.68	N;N
REVEL	Benign	0.21
Sift	Benign	0.64	T;T
Sift4G	Uncertain	0.055	T;T
Polyphen		0.88	P;.
Vest4		0.40
MutPred		0.43		Loss of catalytic residue at V307 (P = 0.0605);Loss of catalytic residue at V307 (P = 0.0605);
MVP		0.18
MPC		0.37
ClinPred		0.27	T
GERP RS		3.6
Varity_R		0.051
gMVP		0.31

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

Publications

LitVar

Other links and lift over

dbSNP: rs201180083; hg19: chr19-42840173;