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GeneBe

rs138235390

chr19-42370784-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.7089C>T(p.Cys2363=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000395 in 1,512,866 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.00033 ( 0 hom., cov: 25)
Exomes 𝑓: 0.00040 ( 1 hom. )

Consequence

MEGF8
NM_001271938.2 synonymous

Scores

1
6

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.453
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]

Genome browser will be placed here

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_addAF=-0.340325).
BP6
?
    BP6 - Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation
Variant 19-42370784-C-T is Benign according to our data. Variant chr19-42370784-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 473344.Status of the report is criteria_provided_single_submitter, 1 stars.
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=-0.453 with no splicing effect.
BS1
?
    BS1 - Allele frequency is greater than expected for disorder
Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000334 (47/140668) while in subpopulation NFE AF= 0.000576 (38/65992). AF 95% confidence interval is 0.000431. There are 0 homozygotes in gnomad4. There are 26 alleles in male gnomad4 subpopulation. This position pass quality control queck.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
MEGF8NM_001271938.2 linkuse as main transcriptc.7089C>T p.Cys2363= synonymous_variant 40/42 ENST00000251268.11
MEGF8NM_001410.3 linkuse as main transcriptc.6888C>T p.Cys2296= synonymous_variant 39/41

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
MEGF8ENST00000251268.11 linkuse as main transcriptc.7089C>T p.Cys2363= synonymous_variant 40/425 NM_001271938.2 A2Q7Z7M0-1

Frequencies

GnomAD3 genomes
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.000334
AC:
47
AN:
140668
Hom.:
0
Cov.:
25
show subpopulations
Gnomad AFR
AF:
0.000159
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000159
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000224
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000576
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000374
AC:
63
AN:
168552
Hom.:
0
AF XY:
0.000304
AC XY:
27
AN XY:
88760
show subpopulations
Gnomad AFR exome
AF:
0.000206
Gnomad AMR exome
AF:
0.000198
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.000173
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000725
Gnomad OTH exome
AF:
0.000643
GnomAD4 exome
AF:
0.000401
AC:
550
AN:
1372198
Hom.:
1
Cov.:
25
AF XY:
0.000387
AC XY:
263
AN XY:
679498
show subpopulations
Gnomad4 AFR exome
AF:
0.0000319
Gnomad4 AMR exome
AF:
0.000192
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.000379
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.000472
Gnomad4 OTH exome
AF:
0.000245
GnomAD4 genome
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.000334
AC:
47
AN:
140668
Hom.:
0
Cov.:
25
AF XY:
0.000385
AC XY:
26
AN XY:
67454
show subpopulations
Gnomad4 AFR
AF:
0.000159
Gnomad4 AMR
AF:
0.000159
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.000224
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000576
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000352
Hom.:
0
Bravo
AF:
0.000332
ESP6500AA
AF:
0.000227
AC:
1
ESP6500EA
AF:
0.000815
AC:
7
ExAC
?
    Exome Aggregation Consortium database
AF:
0.000202
AC:
23

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 testingInvitaeOct 23, 2023- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Benign
-0.34
T
BayesDel_noAF
Benign
-0.35
Cadd
Benign
6.7
Dann
Uncertain
1.0
Eigen
Benign
-0.51
Eigen_PC
Benign
-0.54
FATHMM_MKL
Benign
0.15
N
MutationTaster
Benign
1.0
D;D;D
Vest4
0.34
GERP RS
-1.3
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7

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

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

Other links and lift over

dbSNP: rs138235390; hg19: chr19-42874936; COSMIC: COSV99237755; API