chr19-42376704-A-G

Position:

• chr19-42376704-A-G

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.8467A>G​(p.Ser2823Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00462 in 152,318 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0046 (8 hom., cov: 32)
  • Exomes 𝑓: 0.00041 (3 hom.)
  • Failed GnomAD Quality Control
• Consequence: MEGF8 NM_001271938.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.19

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=0.0046291947).
• BP6: Variant 19-42376704-A-G is Benign according to our data. Variant chr19-42376704-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 445632.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-42376704-A-G is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00462 (704/152318) while in subpopulation AFR AF= 0.016 (666/41572). AF 95% confidence interval is 0.015. There are 8 homozygotes in gnomad4. There are 340 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 8 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MEGF8	NM_001271938.2	c.8467A>G	p.Ser2823Gly	missense_variant	42/42	ENST00000251268.11	NP_001258867.1
MEGF8	NM_001410.3	c.8266A>G	p.Ser2756Gly	missense_variant	41/41		NP_001401.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MEGF8	ENST00000251268.11	c.8467A>G	p.Ser2823Gly	missense_variant	42/42	5	NM_001271938.2	ENSP00000251268.5

Frequencies

GnomAD3 genomes AF: 0.00461 AC: 701 AN: 152202 Hom.: 8 Cov.: 32

Gnomad AFR AF: 0.0160

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00190

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00431

GnomAD3 exomes AF: 0.00110 AC: 130 AN: 118380 Hom.: 1 AF XY: 0.00106 AC XY: 66 AN XY: 62530

Gnomad AFR exome AF: 0.0140

Gnomad AMR exome AF: 0.000892

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000218

Gnomad OTH exome AF: 0.000281

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.000412 AC: 559 AN: 1355198 Hom.: 3 Cov.: 31 AF XY: 0.000380 AC XY: 252 AN XY: 663660

Gnomad4 AFR exome AF: 0.0140

Gnomad4 AMR exome AF: 0.000829

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000245

Gnomad4 OTH exome AF: 0.00115

GnomAD4 genome AF: 0.00462 AC: 704 AN: 152318 Hom.: 8 Cov.: 32 AF XY: 0.00456 AC XY: 340 AN XY: 74496

Gnomad4 AFR AF: 0.0160

Gnomad4 AMR AF: 0.00189

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00427

Alfa AF: 0.000550 Hom.: 1

Bravo AF: 0.00483

ExAC AF: 0.000354 AC: 39

Asia WGS AF: 0.000866 AC: 3 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	clinical testing	GeneDx	Aug 02, 2023	See Variant Classification Assertion Criteria. -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Mar 10, 2017	- -

MEGF8-related Carpenter syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 31, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.055
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	8.2
DANN	Benign	0.94
DEOGEN2	Benign	0.085	.;.;T
Eigen	Benign	-0.59
Eigen_PC	Benign	-0.48
FATHMM_MKL	Benign	0.26	N
LIST_S2	Benign	0.67	T;T;T
MetaRNN	Benign	0.0046	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.34	.;.;N
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-1.1	N;N;N
REVEL	Benign	0.089
Sift	Benign	0.054	T;T;D
Sift4G	Benign	0.11	T;T;D
Polyphen		0.0	B;B;P
Vest4		0.17
MVP		0.18
MPC		0.49
ClinPred		0.0046	T
GERP RS		2.4
Varity_R		0.046
gMVP		0.34

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: rs537269414; hg19: chr19-42880856; COSMIC: COSV52074632; COSMIC: COSV52074632;