rs768036287

chr19-42333743-C-Achr19-42333743-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001271938.2(MEGF8):c.326C>A(p.Pro109Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,626 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P109L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: MEGF8 NM_001271938.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.34

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.047110796).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MEGF8	NM_001271938.2	c.326C>A	p.Pro109Gln	missense_variant	2/42	ENST00000251268.11
MEGF8	NM_001410.3	c.326C>A	p.Pro109Gln	missense_variant	2/41

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MEGF8	ENST00000251268.11	c.326C>A	p.Pro109Gln	missense_variant	2/42	5	NM_001271938.2	A2
MEGF8	ENST00000334370.8	c.326C>A	p.Pro109Gln	missense_variant	2/41	1		P2
MEGF8	ENST00000378073.5	c.-6760C>A		5_prime_UTR_variant	2/41	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000161 AC: 4 AN: 248734 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 134950

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000116

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: 5 AN: 1461626 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727112

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000895

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: 0.0000166

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

ExAC AF: 0.0000165 AC: 2

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.080
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.55
Cadd	Benign	12
Dann	Benign	0.74
Eigen	Benign	-0.81
Eigen_PC	Benign	-0.66
FATHMM_MKL	Benign	0.089	N
LIST_S2	Benign	0.81	T;T
M_CAP	Benign	0.0087	T
MetaRNN	Benign	0.047	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.35	N;N
MutationTaster	Benign	0.98	N;N
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	0.37	N;N
REVEL	Benign	0.065
Sift	Benign	0.72	T;T
Sift4G	Benign	0.43	T;T
Polyphen		0.0030	B;.
Vest4		0.35
MutPred		0.43		Loss of glycosylation at P109 (P = 0.0093);Loss of glycosylation at P109 (P = 0.0093);
MVP		0.043
MPC		0.36
ClinPred		0.054	T
GERP RS		4.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.032
gMVP		0.12

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: rs768036287; hg19: chr19-42837895;