19-42350337-C-T

Variant names:

• chr19-42350337-C-T
• rs777017134
• NM_001271938.2:c.2689C>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001271938.2(MEGF8):​c.2689C>T​(p.Leu897Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000758 in 1,450,816 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000076 (0 hom.)
• Consequence: MEGF8 NM_001271938.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 2.70
• 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: PanelApp Australia, G2P, Ambry Genetics, ClinGen, Labcorp Genetics (formerly Invitae)
• Carpenter syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.21364763).

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MEGF8	NM_001271938.2	MANE Select	c.2689C>T	p.Leu897Phe	missense	Exon 15 of 42	NP_001258867.1
	MEGF8	NM_001410.3		c.2488C>T	p.Leu830Phe	missense	Exon 14 of 41	NP_001401.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MEGF8	ENST00000251268.11	TSL:5 MANE Select	c.2689C>T	p.Leu897Phe	missense	Exon 15 of 42	ENSP00000251268.5
	MEGF8	ENST00000334370.8	TSL:1	c.2488C>T	p.Leu830Phe	missense	Exon 14 of 41	ENSP00000334219.4
	MEGF8	ENST00000378073.5	TSL:5	c.-4397C>T		5_prime_UTR	Exon 15 of 41	ENSP00000367313.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000421 AC: 1 AN: 237338 AF XY: 0.00000772

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000551

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000758 AC: 11 AN: 1450816 Hom.: 0 Cov.: 32 AF XY: 0.00000693 AC XY: 5 AN XY: 721610

African (AFR) AF: 0.00 AC: 0 AN: 33398

American (AMR) AF: 0.0000226 AC: 1 AN: 44288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25880

East Asian (EAS) AF: 0.0000253 AC: 1 AN: 39594

South Asian (SAS) AF: 0.00 AC: 0 AN: 85934

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 46684

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5742

European-Non Finnish (NFE) AF: 9.02e-7 AC: 1 AN: 1109216

Other (OTH) AF: 0.000133 AC: 8 AN: 60080

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000936 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.00000825 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

MEGF8-related Carpenter syndrome Uncertain:1

Apr 24, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals with MEGF8-related disease. This variant is present in population databases (rs777017134, ExAC 0.01%). This sequence change replaces leucine with phenylalanine at codon 830 of the MEGF8 protein (p.Leu830Phe). The leucine residue is highly conserved and there is a small physicochemical difference between leucine and phenylalanine.

Inborn genetic diseases Uncertain:1

Oct 25, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2488C>T (p.L830F) alteration is located in exon 14 (coding exon 14) of the MEGF8 gene. This alteration results from a C to T substitution at nucleotide position 2488, causing the leucine (L) at amino acid position 830 to be replaced by a phenylalanine (F). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.093
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.12	T
Eigen	Benign	0.16
Eigen_PC	Uncertain	0.27
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Uncertain	0.90	D
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.21	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.4	L
PhyloP100		2.7
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.088
Sift	Benign	0.69	T
Sift4G	Benign	0.27	T
Polyphen		0.92	P
Vest4		0.23
MutPred		0.52		Loss of solvent accessibility (P = 0.0159)
MVP		0.093
MPC		1.1
ClinPred		0.80	D
GERP RS		4.9
Varity_R		0.090
gMVP		0.39
Mutation Taster		=82/18	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs777017134; hg19: chr19-42854489;