rs28483598

Variant names:

• chr19-42370748-C-T
• rs28483598
• NM_001271938.2:c.7053C>T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_001271938.2(MEGF8):​c.7053C>T​(p.Cys2351Cys) 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:3
• Conservation: PhyloP100: -0.524
• Publications: 2 publications found

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]

MEGF8 Gene-Disease associations (from GenCC):

• MEGF8-related Carpenter syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: PanelApp Australia, G2P, Ambry Genetics, ClinGen, Labcorp Genetics (formerly Invitae)
• Carpenter syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001271938.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MEGF8	NM_001271938.2	MANE Select	c.7053C>T	p.Cys2351Cys	synonymous	Exon 40 of 42	NP_001258867.1
	MEGF8	NM_001410.3		c.6852C>T	p.Cys2284Cys	synonymous	Exon 39 of 41	NP_001401.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MEGF8	ENST00000251268.11	TSL:5 MANE Select	c.7053C>T	p.Cys2351Cys	synonymous	Exon 40 of 42	ENSP00000251268.5
	MEGF8	ENST00000334370.8	TSL:1	c.6852C>T	p.Cys2284Cys	synonymous	Exon 39 of 41	ENSP00000334219.4
	MEGF8	ENST00000593647.1	TSL:1	c.312C>T	p.Cys104Cys	synonymous	Exon 3 of 4	ENSP00000470620.1

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

GnomAD2 exomes AF: 0.00424 AC: 859 AN: 202810 AF XY: 0.00317

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 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

African (AFR) AF: 0.0605 AC: 1987 AN: 32848

American (AMR) AF: 0.00384 AC: 153 AN: 39832

Ashkenazi Jewish (ASJ) AF: 0.00137 AC: 35 AN: 25568

East Asian (EAS) AF: 0.0000523 AC: 2 AN: 38222

South Asian (SAS) AF: 0.000220 AC: 18 AN: 81674

European-Finnish (FIN) AF: 0.0000194 AC: 1 AN: 51436

Middle Eastern (MID) AF: 0.0152 AC: 87 AN: 5730

European-Non Finnish (NFE) AF: 0.000458 AC: 502 AN: 1096440

Other (OTH) AF: 0.00495 AC: 294 AN: 59368

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

African (AFR) AF: 0.0517 AC: 2123 AN: 41040

American (AMR) AF: 0.00710 AC: 106 AN: 14922

Ashkenazi Jewish (ASJ) AF: 0.00116 AC: 4 AN: 3458

East Asian (EAS) AF: 0.000392 AC: 2 AN: 5096

South Asian (SAS) AF: 0.000211 AC: 1 AN: 4730

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10288

Middle Eastern (MID) AF: 0.0238 AC: 7 AN: 294

European-Non Finnish (NFE) AF: 0.000591 AC: 40 AN: 67626

Other (OTH) AF: 0.0134 AC: 28 AN: 2082

Alfa AF: 0.00791 Hom.: 22

Bravo AF: 0.0176

Asia WGS AF: 0.00664 AC: 24 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	MEGF8-related Carpenter syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.43
CADD	Benign	3.5
DANN	Benign	0.93
PhyloP100		-0.52
Mutation Taster		=83/17	polymorphism

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

Other links and lift over

dbSNP: rs28483598; hg19: chr19-42874900;