rs147216997

chr19-42375910-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001271938.2(MEGF8):c.7673C>T(p.Pro2558Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00752 in 1,599,210 control chromosomes in the GnomAD database, including 45 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). Synonymous variant affecting the same amino acid position (i.e. P2558P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0062 (7 hom., cov: 32)
  • Exomes 𝑓: 0.0077 (38 hom.)
• Consequence: MEGF8 NM_001271938.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:5
• Conservation: PhyloP100: 0.302

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 Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0047466457).
• BP6: Variant 19-42375910-C-T is Benign according to our data. Variant chr19-42375910-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 235520.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Benign=1, Uncertain_significance=1}. Variant chr19-42375910-C-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00615 (937/152302) while in subpopulation NFE AF= 0.01 (681/68012). AF 95% confidence interval is 0.00939. There are 7 homozygotes in gnomad4. There are 412 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 7 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MEGF8	NM_001271938.2	c.7673C>T	p.Pro2558Leu	missense_variant	42/42	ENST00000251268.11
MEGF8	NM_001410.3	c.7472C>T	p.Pro2491Leu	missense_variant	41/41

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MEGF8	ENST00000251268.11	c.7673C>T	p.Pro2558Leu	missense_variant	42/42	5	NM_001271938.2	A2

Frequencies

GnomAD3 genomes AF: 0.00616 AC: 937 AN: 152184 Hom.: 7 Cov.: 32

Gnomad AFR AF: 0.00166

Gnomad AMI AF: 0.0110

Gnomad AMR AF: 0.00386

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.00828

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.0100

Gnomad OTH AF: 0.00574

GnomAD3 exomes AF: 0.00576 AC: 1333 AN: 231274 Hom.: 6 AF XY: 0.00591 AC XY: 751 AN XY: 127128

Gnomad AFR exome AF: 0.00120

Gnomad AMR exome AF: 0.00299

Gnomad ASJ exome AF: 0.00197

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00332

Gnomad FIN exome AF: 0.00860

Gnomad NFE exome AF: 0.00867

Gnomad OTH exome AF: 0.00644

GnomAD4 exome AF: 0.00766 AC: 11085 AN: 1446908 Hom.: 38 Cov.: 31 AF XY: 0.00751 AC XY: 5396 AN XY: 718180

Gnomad4 AFR exome AF: 0.00150

Gnomad4 AMR exome AF: 0.00290

Gnomad4 ASJ exome AF: 0.00206

Gnomad4 EAS exome AF: 0.0000507

Gnomad4 SAS exome AF: 0.00286

Gnomad4 FIN exome AF: 0.00887

Gnomad4 NFE exome AF: 0.00879

Gnomad4 OTH exome AF: 0.00618

GnomAD4 genome AF: 0.00615 AC: 937 AN: 152302 Hom.: 7 Cov.: 32 AF XY: 0.00553 AC XY: 412 AN XY: 74462

Gnomad4 AFR AF: 0.00166

Gnomad4 AMR AF: 0.00385

Gnomad4 ASJ AF: 0.00144

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00145

Gnomad4 FIN AF: 0.00828

Gnomad4 NFE AF: 0.0100

Gnomad4 OTH AF: 0.00568

Alfa AF: 0.00716 Hom.: 2

Bravo AF: 0.00506

TwinsUK AF: 0.00647 AC: 24

ALSPAC AF: 0.00752 AC: 29

ESP6500AA AF: 0.00208 AC: 9

ESP6500EA AF: 0.00696 AC: 59

ExAC AF: 0.00569 AC: 685

Asia WGS AF: 0.00173 AC: 6 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	MEGF8: BS2 -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	May 16, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	May 04, 2020	- -

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 18, 2021

The c.7472C>T (p.P2491L) alteration is located in exon 41 (coding exon 41) of the MEGF8 gene. This alteration results from a C to T substitution at nucleotide position 7472, causing the proline (P) at amino acid position 2491 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

MEGF8-related Carpenter syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

MEGF8-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 16, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.097
BayesDel_addAF	Benign	-0.65	T
BayesDel_noAF	Benign	-0.70
Cadd	Benign	5.2
Dann	Benign	0.43
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.75	T;T;T
MetaRNN	Benign	0.0047	T;T;T
MetaSVM	Benign	-0.96	T
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-1.6	N;N;N
REVEL	Benign	0.043
Sift	Benign	0.38	T;T;T
Sift4G	Benign	0.083	T;D;T
Polyphen		0.0030	B;B;B
Vest4		0.17
MVP		0.043
MPC		0.55
ClinPred		0.0039	T
GERP RS		0.090
Varity_R		0.037
gMVP		0.37

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

Other links and lift over

dbSNP: rs147216997; hg19: chr19-42880062; COSMIC: COSV52084922;