rs112167630

Positions:

• chr19-42370749-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001271938.2(MEGF8):​c.7054G>A​(p.Val2352Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0228 in 1,581,696 control chromosomes in the GnomAD database, including 500 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.016 (31 hom., cov: 27)
  • Exomes 𝑓: 0.024 (469 hom.)
• Consequence: MEGF8 NM_001271938.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 7.54

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008328646).
• BP6: Variant 19-42370749-G-A is Benign according to our data. Variant chr19-42370749-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 473343.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-42370749-G-A is described in Lovd as [Likely_benign]. Variant chr19-42370749-G-A is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0163 (2454/150866) while in subpopulation NFE AF= 0.0246 (1662/67610). AF 95% confidence interval is 0.0236. There are 31 homozygotes in gnomad4. There are 1177 alleles in male gnomad4 subpopulation. Median coverage is 27. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 31 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MEGF8	NM_001271938.2	c.7054G>A	p.Val2352Met	missense_variant	40/42	ENST00000251268.11
MEGF8	NM_001410.3	c.6853G>A	p.Val2285Met	missense_variant	39/41

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MEGF8	ENST00000251268.11	c.7054G>A	p.Val2352Met	missense_variant	40/42	5	NM_001271938.2	A2

Frequencies

GnomAD3 genomes AF: 0.0163 AC: 2455 AN: 150752 Hom.: 31 Cov.: 27

Gnomad AFR AF: 0.00411

Gnomad AMI AF: 0.0220

Gnomad AMR AF: 0.00640

Gnomad ASJ AF: 0.0309

Gnomad EAS AF: 0.000195

Gnomad SAS AF: 0.00189

Gnomad FIN AF: 0.0341

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.0246

Gnomad OTH AF: 0.0165

GnomAD3 exomes AF: 0.0179 AC: 3632 AN: 202642 Hom.: 49 AF XY: 0.0182 AC XY: 1967 AN XY: 108064

Gnomad AFR exome AF: 0.00316

Gnomad AMR exome AF: 0.00538

Gnomad ASJ exome AF: 0.0326

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00210

Gnomad FIN exome AF: 0.0362

Gnomad NFE exome AF: 0.0261

Gnomad OTH exome AF: 0.0208

GnomAD4 exome AF: 0.0235 AC: 33649 AN: 1430830 Hom.: 469 Cov.: 31 AF XY: 0.0228 AC XY: 16184 AN XY: 708736

Gnomad4 AFR exome AF: 0.00338

Gnomad4 AMR exome AF: 0.00567

Gnomad4 ASJ exome AF: 0.0352

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00212

Gnomad4 FIN exome AF: 0.0359

Gnomad4 NFE exome AF: 0.0267

Gnomad4 OTH exome AF: 0.0187

GnomAD4 genome AF: 0.0163 AC: 2454 AN: 150866 Hom.: 31 Cov.: 27 AF XY: 0.0160 AC XY: 1177 AN XY: 73644

Gnomad4 AFR AF: 0.00410

Gnomad4 AMR AF: 0.00645

Gnomad4 ASJ AF: 0.0309

Gnomad4 EAS AF: 0.000196

Gnomad4 SAS AF: 0.00189

Gnomad4 FIN AF: 0.0341

Gnomad4 NFE AF: 0.0246

Gnomad4 OTH AF: 0.0163

Alfa AF: 0.0219 Hom.: 27

Bravo AF: 0.0142

TwinsUK AF: 0.0270 AC: 100

ALSPAC AF: 0.0288 AC: 111

ESP6500AA AF: 0.00477 AC: 21

ESP6500EA AF: 0.0248 AC: 213

ExAC AF: 0.0161 AC: 1944

Asia WGS AF: 0.00173 AC: 6 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 21, 2021	- -

MEGF8-related Carpenter syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 24, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.30
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.17	.;T;.
Eigen	Pathogenic	0.70
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.95	D;D;D
MetaRNN	Benign	0.0083	T;T;T
MetaSVM	Benign	-0.35	T
MutationAssessor	Uncertain	2.2	.;M;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	-1.4	N;N;.
REVEL	Uncertain	0.30
Sift	Uncertain	0.0060	D;D;.
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	D;D;.
Vest4		0.42
MPC		1.5
ClinPred		0.0086	T
GERP RS		4.9
Varity_R		0.30
gMVP		0.55

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: rs112167630; hg19: chr19-42874901; COSMIC: COSV99044067;