rs397515428

chr19-42375537-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP5 BP4

The NM_001271938.2(MEGF8):c.7300A>G(p.Ser2434Gly) 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. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: MEGF8 NM_001271938.2 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 5.33

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 19-42375537-A-G is Pathogenic according to our data. Variant chr19-42375537-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 39846.Status of the report is no_assertion_criteria_provided, 0 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.11740446).. Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MEGF8	NM_001271938.2	c.7300A>G	p.Ser2434Gly	missense_variant	42/42	ENST00000251268.11
MEGF8	NM_001410.3	c.7099A>G	p.Ser2367Gly	missense_variant	41/41

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MEGF8	ENST00000251268.11	c.7300A>G	p.Ser2434Gly	missense_variant	42/42	5	NM_001271938.2	A2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.00152 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

MEGF8-related Carpenter syndrome Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Nov 02, 2012

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.52
Cadd	Benign	22
Dann	Uncertain	0.98
Eigen	Benign	-0.10
Eigen_PC	Benign	-0.012
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.80	T;T;T
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.12	T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	0.78	D;D;D
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-1.7	N;N;N
REVEL	Benign	0.043
Sift	Benign	0.20	T;T;T
Sift4G	Uncertain	0.024	D;D;T
Polyphen		0.60	P;B;B
Vest4		0.17
MutPred		0.25		.;.;Loss of glycosylation at S2434 (P = 0.0503);
MVP		0.14
MPC		0.51
ClinPred		0.80	D
GERP RS		4.5
Varity_R		0.11
gMVP		0.64

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: rs397515428; hg19: chr19-42879689;