19-42370736-C-G

Variant names:

• chr19-42370736-C-G
• rs145886667
• NM_001271938.2:c.7041C>G

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.7041C>G​(p.Asp2347Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000696 in 1,437,316 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign 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. D2347D) 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: -2.75
• 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.10321581).

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.7041C>G	p.Asp2347Glu	missense	Exon 40 of 42	NP_001258867.1	Q7Z7M0-1
	MEGF8	NM_001410.3		c.6840C>G	p.Asp2280Glu	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.7041C>G	p.Asp2347Glu	missense	Exon 40 of 42	ENSP00000251268.5	Q7Z7M0-1
	MEGF8	ENST00000334370.8	TSL:1	c.6840C>G	p.Asp2280Glu	missense	Exon 39 of 41	ENSP00000334219.4	Q7Z7M0-2
	MEGF8	ENST00000593647.1	TSL:1	c.300C>G	p.Asp100Glu	missense	Exon 3 of 4	ENSP00000470620.1	M0QZL2

Frequencies

GnomAD3 genomes Cov.: 27

GnomAD4 exome AF: 6.96e-7 AC: 1 AN: 1437316 Hom.: 0 Cov.: 32 AF XY: 0.00000140 AC XY: 1 AN XY: 712460

African (AFR) AF: 0.00 AC: 0 AN: 33004

American (AMR) AF: 0.00 AC: 0 AN: 40826

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25656

East Asian (EAS) AF: 0.00 AC: 0 AN: 38618

South Asian (SAS) AF: 0.00 AC: 0 AN: 82238

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51768

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5736

European-Non Finnish (NFE) AF: 9.09e-7 AC: 1 AN: 1099880

Other (OTH) AF: 0.00 AC: 0 AN: 59590

GnomAD4 genome Cov.: 27

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	0.0030
DANN	Uncertain	0.98
DEOGEN2	Benign	0.10	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.064	N
LIST_S2	Benign	0.78	T
M_CAP	Benign	0.053	D
MetaRNN	Benign	0.10	T
MetaSVM	Benign	-0.40	T
MutationAssessor	Benign	-0.035	N
PhyloP100		-2.7
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-1.5	N
REVEL	Benign	0.12
Sift	Uncertain	0.013	D
Sift4G	Benign	0.23	T
Polyphen		0.28	B
Vest4		0.22
MutPred		0.27		Gain of disorder (P = 0.077)
MVP		0.15
MPC		0.51
ClinPred		0.69	D
GERP RS		-8.4
Varity_R		0.075
gMVP		0.52
Mutation Taster		=67/33	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: rs145886667; hg19: chr19-42874888;