19-42370749-G-T

Variant names:

• chr19-42370749-G-T
• NM_001271938.2:c.7054G>T

Variant summary

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

The NM_001271938.2(MEGF8):​c.7054G>T​(p.Val2352Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000699 in 1,430,994 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. V2352M) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 27)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: MEGF8 NM_001271938.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.54

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MEGF8	NM_001271938.2	c.7054G>T	p.Val2352Leu	missense_variant	Exon 40 of 42	ENST00000251268.11	NP_001258867.1
MEGF8	NM_001410.3	c.6853G>T	p.Val2285Leu	missense_variant	Exon 39 of 41		NP_001401.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MEGF8	ENST00000251268.11	c.7054G>T	p.Val2352Leu	missense_variant	Exon 40 of 42	5	NM_001271938.2	ENSP00000251268.5

Frequencies

GnomAD3 genomes Cov.: 27

GnomAD4 exome AF: 6.99e-7 AC: 1 AN: 1430994 Hom.: 0 Cov.: 31 AF XY: 0.00000141 AC XY: 1 AN XY: 708826

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000262

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.: 27

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.28
BayesDel_addAF	Benign	-0.021	T
BayesDel_noAF	Benign	-0.27
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.066	.;T;.
Eigen	Uncertain	0.41
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.92	D;D;D
M_CAP	Benign	0.069	D
MetaRNN	Uncertain	0.58	D;D;D
MetaSVM	Benign	-0.85	T
MutationAssessor	Benign	1.1	.;L;.
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-0.65	N;N;.
REVEL	Benign	0.24
Sift	Benign	0.31	T;T;.
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	D;D;.
Vest4		0.46
MutPred		0.71		.;Gain of disorder (P = 0.1848);.;
MVP		0.48
MPC		0.81
ClinPred		0.95	D
GERP RS		4.9
Varity_R		0.23
gMVP		0.58

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-42874901;