rs11881304

chr19-42376663-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.8426G>A(p.Arg2809Lys) variant causes a missense change. The variant allele was found at a frequency of 0.0015 in 1,534,696 control chromosomes in the GnomAD database, including 32 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0080 (19 hom., cov: 32)
  • Exomes 𝑓: 0.00078 (13 hom.)
• Consequence: MEGF8 NM_001271938.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 6.53

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=0.0028442144).
• BP6: Variant 19-42376663-G-A is Benign according to our data. Variant chr19-42376663-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 473352.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00798 (1216/152370) while in subpopulation AFR AF= 0.0274 (1140/41586). AF 95% confidence interval is 0.0261. There are 19 homozygotes in gnomad4. There are 558 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 19 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MEGF8	NM_001271938.2	c.8426G>A	p.Arg2809Lys	missense_variant	42/42	ENST00000251268.11
MEGF8	NM_001410.3	c.8225G>A	p.Arg2742Lys	missense_variant	41/41

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MEGF8	ENST00000251268.11	c.8426G>A	p.Arg2809Lys	missense_variant	42/42	5	NM_001271938.2	A2

Frequencies

GnomAD3 genomes AF: 0.00796 AC: 1212 AN: 152252 Hom.: 19 Cov.: 32

Gnomad AFR AF: 0.0274

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00373

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: 0.0000588

Gnomad OTH AF: 0.00717

GnomAD3 exomes AF: 0.00166 AC: 226 AN: 136352 Hom.: 5 AF XY: 0.00131 AC XY: 96 AN XY: 73470

Gnomad AFR exome AF: 0.0232

Gnomad AMR exome AF: 0.00194

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000484

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000763

Gnomad OTH exome AF: 0.000495

GnomAD4 exome AF: 0.000783 AC: 1082 AN: 1382326 Hom.: 13 Cov.: 31 AF XY: 0.000704 AC XY: 479 AN XY: 680622

Gnomad4 AFR exome AF: 0.0262

Gnomad4 AMR exome AF: 0.00205

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000515

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000549

Gnomad4 OTH exome AF: 0.00197

GnomAD4 genome AF: 0.00798 AC: 1216 AN: 152370 Hom.: 19 Cov.: 32 AF XY: 0.00749 AC XY: 558 AN XY: 74512

Gnomad4 AFR AF: 0.0274

Gnomad4 AMR AF: 0.00372

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.00710

Alfa AF: 0.00170 Hom.: 49

Bravo AF: 0.00884

ESP6500AA AF: 0.0163 AC: 69

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00137 AC: 150

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

Significance: Benign/Likely 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

Dec 02, 2023

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Jul 09, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.55
Cadd	Uncertain	23
Dann	Uncertain	0.99
Eigen	Benign	-0.051
Eigen_PC	Benign	0.12
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Benign	0.83	T;T;T
MetaRNN	Benign	0.0028	T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	0.89	N;N;N
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	-0.92	N;N;N
REVEL	Benign	0.082
Sift	Benign	0.085	T;T;T
Sift4G	Benign	0.84	T;T;T
Polyphen		0.60	P;B;P
Vest4		0.14
MVP		0.043
MPC		1.0
ClinPred		0.018	T
GERP RS		4.5
Varity_R		0.16
gMVP		0.54

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: rs11881304; hg19: chr19-42880815;