19-42370749-G-T

Variant names:

• chr19-42370749-G-T
• rs112167630
• NM_001271938.2:c.7054G>T

Variant summary

Our verdict is Uncertain significance. The variant received 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
• 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: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P, ClinGen
• Carpenter syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001271938.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MEGF8	NM_001271938.2	MANE Select	c.7054G>T	p.Val2352Leu	missense	Exon 40 of 42	NP_001258867.1	Q7Z7M0-1
	MEGF8	NM_001410.3		c.6853G>T	p.Val2285Leu	missense	Exon 39 of 41	NP_001401.2	Q7Z7M0-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MEGF8	ENST00000251268.11	TSL:5 MANE Select	c.7054G>T	p.Val2352Leu	missense	Exon 40 of 42	ENSP00000251268.5	Q7Z7M0-1
	MEGF8	ENST00000334370.8	TSL:1	c.6853G>T	p.Val2285Leu	missense	Exon 39 of 41	ENSP00000334219.4	Q7Z7M0-2
	MEGF8	ENST00000593647.1	TSL:1	c.313G>T	p.Val105Leu	missense	Exon 3 of 4	ENSP00000470620.1	M0QZL2

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

African (AFR) AF: 0.00 AC: 0 AN: 32830

American (AMR) AF: 0.00 AC: 0 AN: 39840

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25568

East Asian (EAS) AF: 0.0000262 AC: 1 AN: 38222

South Asian (SAS) AF: 0.00 AC: 0 AN: 81676

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51424

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5730

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1096360

Other (OTH) AF: 0.00 AC: 0 AN: 59344

GnomAD4 genome Cov.: 27

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

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
M_CAP	Benign	0.069	D
MetaRNN	Uncertain	0.58	D
MetaSVM	Benign	-0.85	T
MutationAssessor	Benign	1.1	L
PhyloP100		7.5
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-0.65	N
REVEL	Benign	0.24
Sift	Benign	0.31	T
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	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
Mutation Taster		=228/72	polymorphism

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: rs112167630; hg19: chr19-42874901;