19-42370784-C-G

Variant names:

• chr19-42370784-C-G
• rs138235390
• NM_001271938.2:c.7089C>G

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_001271938.2(MEGF8):​c.7089C>G​(p.Cys2363Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000729 in 1,372,208 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. C2363C) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 25)
  • Exomes 𝑓: 7.3e-7 (0 hom.)
• Consequence: MEGF8 NM_001271938.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.453
• 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: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.965

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.7089C>G	p.Cys2363Trp	missense	Exon 40 of 42	NP_001258867.1	Q7Z7M0-1
	MEGF8	NM_001410.3		c.6888C>G	p.Cys2296Trp	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.7089C>G	p.Cys2363Trp	missense	Exon 40 of 42	ENSP00000251268.5	Q7Z7M0-1
	MEGF8	ENST00000334370.8	TSL:1	c.6888C>G	p.Cys2296Trp	missense	Exon 39 of 41	ENSP00000334219.4	Q7Z7M0-2
	MEGF8	ENST00000593647.1	TSL:1	c.348C>G	p.Cys116Trp	missense	Exon 3 of 4	ENSP00000470620.1	M0QZL2

Frequencies

GnomAD3 genomes Cov.: 25

GnomAD4 exome AF: 7.29e-7 AC: 1 AN: 1372208 Hom.: 0 Cov.: 25 AF XY: 0.00 AC XY: 0 AN XY: 679502

African (AFR) AF: 0.00 AC: 0 AN: 31376

American (AMR) AF: 0.00 AC: 0 AN: 36416

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24990

East Asian (EAS) AF: 0.00 AC: 0 AN: 36230

South Asian (SAS) AF: 0.00 AC: 0 AN: 79140

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49770

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5594

European-Non Finnish (NFE) AF: 9.51e-7 AC: 1 AN: 1051524

Other (OTH) AF: 0.00 AC: 0 AN: 57168

GnomAD4 genome Cov.: 25

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.15
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.45	T
Eigen	Benign	0.036
Eigen_PC	Benign	-0.13
FATHMM_MKL	Benign	0.36	N
LIST_S2	Uncertain	0.88	D
M_CAP	Uncertain	0.27	D
MetaRNN	Pathogenic	0.96	D
MetaSVM	Benign	-0.79	T
MutationAssessor	Uncertain	2.5	M
PhyloP100		-0.45
PrimateAI	Pathogenic	0.81	D
PROVEAN	Pathogenic	-11	D
REVEL	Pathogenic	0.72
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.71
MutPred		0.87		Loss of methylation at K2362 (P = 0.0238)
MVP		0.40
MPC		1.7
ClinPred		1.0	D
GERP RS		-1.3
Varity_R		0.99
gMVP		0.99
Mutation Taster		=23/77	disease causing

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: rs138235390; hg19: chr19-42874936;