rs28483598

Positions:

• chr19-42370748-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_001271938.2(MEGF8):​c.7053C>T​(p.Cys2351=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00341 in 1,581,566 control chromosomes in the GnomAD database, including 130 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.015 (59 hom., cov: 27)
  • Exomes 𝑓: 0.0022 (71 hom.)
• Consequence: MEGF8 NM_001271938.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.524

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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.43).
• BP6: Variant 19-42370748-C-T is Benign according to our data. Variant chr19-42370748-C-T is described in ClinVar as [Benign]. Clinvar id is 473342.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.524 with no splicing effect.
• BA1: GnomAdExome4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0583 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MEGF8	NM_001271938.2	c.7053C>T	p.Cys2351=	synonymous_variant	40/42	ENST00000251268.11
MEGF8	NM_001410.3	c.6852C>T	p.Cys2284=	synonymous_variant	39/41

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MEGF8	ENST00000251268.11	c.7053C>T	p.Cys2351=	synonymous_variant	40/42	5	NM_001271938.2	A2

Frequencies

GnomAD3 genomes AF: 0.0153 AC: 2307 AN: 150332 Hom.: 58 Cov.: 27

Gnomad AFR AF: 0.0518

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00711

Gnomad ASJ AF: 0.00116

Gnomad EAS AF: 0.000392

Gnomad SAS AF: 0.000211

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.000591

Gnomad OTH AF: 0.0136

GnomAD3 exomes AF: 0.00424 AC: 859 AN: 202810 Hom.: 15 AF XY: 0.00317 AC XY: 343 AN XY: 108230

Gnomad AFR exome AF: 0.0525

Gnomad AMR exome AF: 0.00348

Gnomad ASJ exome AF: 0.00164

Gnomad EAS exome AF: 0.000134

Gnomad SAS exome AF: 0.000278

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000738

Gnomad OTH exome AF: 0.00416

GnomAD4 exome AF: 0.00215 AC: 3079 AN: 1431118 Hom.: 71 Cov.: 31 AF XY: 0.00197 AC XY: 1394 AN XY: 708996

Gnomad4 AFR exome AF: 0.0605

Gnomad4 AMR exome AF: 0.00384

Gnomad4 ASJ exome AF: 0.00137

Gnomad4 EAS exome AF: 0.0000523

Gnomad4 SAS exome AF: 0.000220

Gnomad4 FIN exome AF: 0.0000194

Gnomad4 NFE exome AF: 0.000458

Gnomad4 OTH exome AF: 0.00495

GnomAD4 genome AF: 0.0154 AC: 2311 AN: 150448 Hom.: 59 Cov.: 27 AF XY: 0.0150 AC XY: 1099 AN XY: 73348

Gnomad4 AFR AF: 0.0517

Gnomad4 AMR AF: 0.00710

Gnomad4 ASJ AF: 0.00116

Gnomad4 EAS AF: 0.000392

Gnomad4 SAS AF: 0.000211

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000591

Gnomad4 OTH AF: 0.0134

Alfa AF: 0.00728 Hom.: 18

Bravo AF: 0.0176

Asia WGS AF: 0.00664 AC: 24 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

MEGF8-related Carpenter syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Sep 29, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.43
CADD	Benign	3.5
DANN	Benign	0.93

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: rs28483598; hg19: chr19-42874900; COSMIC: COSV104379518;