rs372350131
Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2BP4_StrongBS1_Supporting
The NM_001271938.2(MEGF8):c.6500C>T(p.Pro2167Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000179 in 1,613,640 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_001271938.2 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -3 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MEGF8 | NM_001271938.2 | c.6500C>T | p.Pro2167Leu | missense_variant | 37/42 | ENST00000251268.11 | |
MEGF8 | NM_001410.3 | c.6299C>T | p.Pro2100Leu | missense_variant | 36/41 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MEGF8 | ENST00000251268.11 | c.6500C>T | p.Pro2167Leu | missense_variant | 37/42 | 5 | NM_001271938.2 | A2 | |
MEGF8 | ENST00000334370.8 | c.6299C>T | p.Pro2100Leu | missense_variant | 36/41 | 1 | P2 | ||
MEGF8 | ENST00000378073.5 | c.-586C>T | 5_prime_UTR_variant | 37/41 | 5 | ||||
MEGF8 | ENST00000598762.1 | c.161+6648C>T | intron_variant | 3 |
Frequencies
GnomAD3 genomes ? AF: 0.0000723 AC: 11AN: 152144Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000224 AC: 56AN: 250392Hom.: 0 AF XY: 0.000288 AC XY: 39AN XY: 135322
GnomAD4 exome AF: 0.000190 AC: 278AN: 1461378Hom.: 1 Cov.: 33 AF XY: 0.000224 AC XY: 163AN XY: 726980
GnomAD4 genome ? AF: 0.0000722 AC: 11AN: 152262Hom.: 0 Cov.: 32 AF XY: 0.0000403 AC XY: 3AN XY: 74452
ClinVar
Submissions by phenotype
not provided Uncertain:1Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jul 30, 2019 | In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge - |
Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Apr 01, 2023 | MEGF8: BP4 - |
MEGF8-related Carpenter syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Sep 21, 2021 | 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 (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. This variant has not been reported in the literature in individuals affected with MEGF8-related conditions. This variant is present in population databases (rs372350131, ExAC 0.1%). This sequence change replaces proline with leucine at codon 2100 of the MEGF8 protein (p.Pro2100Leu). The proline residue is moderately conserved and there is a moderate physicochemical difference between proline and leucine. - |
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | May 27, 2022 | The c.6299C>T (p.P2100L) alteration is located in exon 36 (coding exon 36) of the MEGF8 gene. This alteration results from a C to T substitution at nucleotide position 6299, causing the proline (P) at amino acid position 2100 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at