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GeneBe

19-42376508-C-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 2P and 11B. PM2BP4_StrongBP6_ModerateBP7BS1

The NM_001271938.2(MEGF8):c.8271C>T(p.Pro2757=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000205 in 1,582,750 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.00038 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00019 ( 0 hom. )

Consequence

MEGF8
NM_001271938.2 synonymous

Scores

2

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: -1.08
Variant links:
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]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

PM2
?
    PM2 - Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium
Very rare variant in population databases, with high coverage;
BP4
?
    BP4 - Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc.)
Computational evidence support a benign effect (BayesDel_noAF=-0.77).
BP6
?
    BP6 - Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation
Variant 19-42376508-C-T is Benign according to our data. Variant chr19-42376508-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 540555.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr19-42376508-C-T is described in Lovd as [Likely_benign].
BP7
?
    BP7 - A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved
Synonymous conserved (PhyloP=-1.08 with no splicing effect.
BS1
?
    BS1 - Allele frequency is greater than expected for disorder
Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.000381 (58/152338) while in subpopulation AMR AF= 0.00157 (24/15314). AF 95% confidence interval is 0.00108. There are 0 homozygotes in gnomad4. There are 15 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
MEGF8NM_001271938.2 linkuse as main transcriptc.8271C>T p.Pro2757= synonymous_variant 42/42 ENST00000251268.11
MEGF8NM_001410.3 linkuse as main transcriptc.8070C>T p.Pro2690= synonymous_variant 41/41

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
MEGF8ENST00000251268.11 linkuse as main transcriptc.8271C>T p.Pro2757= synonymous_variant 42/425 NM_001271938.2 A2Q7Z7M0-1

Frequencies

GnomAD3 genomes
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.000342
AC:
52
AN:
152220
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.000169
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00157
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00116
Gnomad SAS
AF:
0.000207
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000162
Gnomad OTH
AF:
0.00144
GnomAD3 exomes
AF:
0.000163
AC:
31
AN:
190374
Hom.:
0
AF XY:
0.000124
AC XY:
13
AN XY:
105042
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.000140
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.000365
Gnomad SAS exome
AF:
0.0000758
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000195
Gnomad OTH exome
AF:
0.000802
GnomAD4 exome
AF:
0.000186
AC:
266
AN:
1430412
Hom.:
0
Cov.:
31
AF XY:
0.000170
AC XY:
121
AN XY:
709800
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.000226
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.000400
Gnomad4 SAS exome
AF:
0.0000241
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.000166
Gnomad4 OTH exome
AF:
0.000979
GnomAD4 genome
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.000381
AC:
58
AN:
152338
Hom.:
0
Cov.:
32
AF XY:
0.000201
AC XY:
15
AN XY:
74490
show subpopulations
Gnomad4 AFR
AF:
0.000168
Gnomad4 AMR
AF:
0.00157
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00116
Gnomad4 SAS
AF:
0.000207
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000162
Gnomad4 OTH
AF:
0.00426
Alfa
AF:
0.000180
Hom.:
0
Bravo
AF:
0.000257
Asia WGS
AF:
0.0160
AC:
57
AN:
3478

ClinVar

Significance: Likely benign
Submissions summary: Benign:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

MEGF8-related Carpenter syndrome Benign:1
Likely benign, criteria provided, single submitterclinical testingInvitaeJan 18, 2024- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.77
Cadd
Benign
3.4
Dann
Benign
0.51

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs755400663; hg19: chr19-42880660; COSMIC: COSV99235344; COSMIC: COSV99235344; API