NM_001271938.2:c.112C>T

Variant names:

• chr19-42326355-C-T
• rs1339893627
• NM_001271938.2:c.112C>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001271938.2(MEGF8):​c.112C>T​(p.Arg38Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: MEGF8 NM_001271938.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.01
• Publications: 1 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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.38588035).

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.112C>T	p.Arg38Trp	missense	Exon 1 of 42	NP_001258867.1	Q7Z7M0-1
	MEGF8	NM_001410.3		c.112C>T	p.Arg38Trp	missense	Exon 1 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.112C>T	p.Arg38Trp	missense	Exon 1 of 42	ENSP00000251268.5	Q7Z7M0-1
	MEGF8	ENST00000334370.8	TSL:1	c.112C>T	p.Arg38Trp	missense	Exon 1 of 41	ENSP00000334219.4	Q7Z7M0-2
	MEGF8	ENST00000378073.5	TSL:5	c.-6974C>T		5_prime_UTR	Exon 1 of 41	ENSP00000367313.4	F5GZG7

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1433430 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 713472

African (AFR) AF: 0.00 AC: 0 AN: 31158

American (AMR) AF: 0.00 AC: 0 AN: 38088

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25212

East Asian (EAS) AF: 0.00 AC: 0 AN: 37238

South Asian (SAS) AF: 0.00 AC: 0 AN: 82752

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52660

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5678

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1101500

Other (OTH) AF: 0.00 AC: 0 AN: 59144

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000151

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	MEGF8-related Carpenter syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Benign	-0.0036	T
BayesDel_noAF	Benign	-0.24
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.24	T
Eigen	Uncertain	0.52
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Benign	0.57	D
LIST_S2	Uncertain	0.96	D
M_CAP	Uncertain	0.093	D
MetaRNN	Benign	0.39	T
MetaSVM	Benign	-0.44	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		2.0
PrimateAI	Uncertain	0.77	T
PROVEAN	Uncertain	-2.9	D
REVEL	Uncertain	0.36
Sift	Uncertain	0.017	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.35
MutPred		0.66		Loss of disorder (P = 0.026)
MVP		0.37
MPC		1.2
ClinPred		1.0	D
GERP RS		4.5
Varity_R		0.23
gMVP		0.63
Mutation Taster		=36/64	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: rs1339893627; hg19: chr19-42830507;