chr19-42344573-C-T

Position:

• chr19-42344573-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001271938.2(MEGF8):​c.1921C>T​(p.Leu641Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000139 in 1,441,984 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 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: 0.0000014 (0 hom.)
• Consequence: MEGF8 NM_001271938.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.931

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.23813698).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MEGF8	NM_001271938.2	c.1921C>T	p.Leu641Phe	missense_variant	11/42	ENST00000251268.11	NP_001258867.1
MEGF8	NM_001410.3	c.1921C>T	p.Leu641Phe	missense_variant	11/41		NP_001401.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MEGF8	ENST00000251268.11	c.1921C>T	p.Leu641Phe	missense_variant	11/42	5	NM_001271938.2	ENSP00000251268	A2
MEGF8	ENST00000334370.8	c.1921C>T	p.Leu641Phe	missense_variant	11/41	1		ENSP00000334219	P2
MEGF8	ENST00000378073.5	c.-5165C>T		5_prime_UTR_variant	11/41	5		ENSP00000367313

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000139 AC: 2 AN: 1441984 Hom.: 0 Cov.: 31 AF XY: 0.00000140 AC XY: 1 AN XY: 716356

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000117

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.05e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

MEGF8-related Carpenter syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 06, 2022

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 are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 540547). This variant has not been reported in the literature in individuals affected with MEGF8-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 641 of the MEGF8 protein (p.Leu641Phe). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.56
CADD	Uncertain	24
DANN	Benign	0.88
DEOGEN2	Benign	0.086	.;T
Eigen	Benign	0.076
Eigen_PC	Benign	0.12
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Uncertain	0.90	D;D
M_CAP	Benign	0.021	T
MetaRNN	Benign	0.24	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.4	L;L
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.73	T
PROVEAN	Benign	-0.59	N;N
REVEL	Benign	0.088
Sift	Benign	0.18	T;T
Sift4G	Uncertain	0.014	D;D
Polyphen		0.96	D;D
Vest4		0.48
MutPred		0.44		Gain of sheet (P = 0.0149);Gain of sheet (P = 0.0149);
MVP		0.043
MPC		1.1
ClinPred		0.69	D
GERP RS		4.6
Varity_R		0.040
gMVP		0.42

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

Publications

LitVar

Other links and lift over

dbSNP: rs1555781030; hg19: chr19-42848725;