chr19-42375942-G-A

Variant names:

• chr19-42375942-G-A
• rs147133204
• NM_001271938.2:c.7705G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001271938.2(MEGF8):​c.7705G>A​(p.Val2569Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00396 in 1,604,188 control chromosomes in the GnomAD database, including 19 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0025 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0041 (17 hom.)
• Consequence: MEGF8 NM_001271938.2 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 9.12
• Publications: 9 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.005036235).
• BP6: Variant 19-42375942-G-A is Benign according to our data. Variant chr19-42375942-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 473348.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00251 (382/152298) while in subpopulation NFE AF = 0.00423 (288/68030). AF 95% confidence interval is 0.00383. There are 2 homozygotes in GnomAd4. There are 168 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

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.7705G>A	p.Val2569Ile	missense	Exon 42 of 42	NP_001258867.1
	MEGF8	NM_001410.3		c.7504G>A	p.Val2502Ile	missense	Exon 41 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.7705G>A	p.Val2569Ile	missense	Exon 42 of 42	ENSP00000251268.5
	MEGF8	ENST00000334370.8	TSL:1	c.7504G>A	p.Val2502Ile	missense	Exon 41 of 41	ENSP00000334219.4
	MEGF8	ENST00000593647.1	TSL:1	c.*294G>A		3_prime_UTR	Exon 4 of 4	ENSP00000470620.1

Frequencies

GnomAD3 genomes AF: 0.00251 AC: 382 AN: 152180 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000989

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00242

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00207

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00423

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.00258 AC: 613 AN: 237494 AF XY: 0.00270

Gnomad AFR exome AF: 0.000675

Gnomad AMR exome AF: 0.00234

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000253

Gnomad NFE exome AF: 0.00421

Gnomad OTH exome AF: 0.00258

GnomAD4 exome AF: 0.00411 AC: 5963 AN: 1451890 Hom.: 17 Cov.: 31 AF XY: 0.00415 AC XY: 2993 AN XY: 721482

African (AFR) AF: 0.000900 AC: 30 AN: 33322

American (AMR) AF: 0.00234 AC: 103 AN: 44110

Ashkenazi Jewish (ASJ) AF: 0.0000390 AC: 1 AN: 25626

East Asian (EAS) AF: 0.00 AC: 0 AN: 39562

South Asian (SAS) AF: 0.00155 AC: 132 AN: 85320

European-Finnish (FIN) AF: 0.000336 AC: 17 AN: 50616

Middle Eastern (MID) AF: 0.000698 AC: 4 AN: 5728

European-Non Finnish (NFE) AF: 0.00493 AC: 5461 AN: 1107624

Other (OTH) AF: 0.00358 AC: 215 AN: 59982

GnomAD4 genome AF: 0.00251 AC: 382 AN: 152298 Hom.: 2 Cov.: 32 AF XY: 0.00226 AC XY: 168 AN XY: 74460

African (AFR) AF: 0.000986 AC: 41 AN: 41566

American (AMR) AF: 0.00242 AC: 37 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5156

South Asian (SAS) AF: 0.00207 AC: 10 AN: 4832

European-Finnish (FIN) AF: 0.0000942 AC: 1 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00423 AC: 288 AN: 68030

Other (OTH) AF: 0.00237 AC: 5 AN: 2112

Alfa AF: 0.00369 Hom.: 4

Bravo AF: 0.00268

TwinsUK AF: 0.00431 AC: 16

ALSPAC AF: 0.00467 AC: 18

ESP6500AA AF: 0.000688 AC: 3

ESP6500EA AF: 0.00269 AC: 23

ExAC AF: 0.00252 AC: 304

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:5

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

May 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

MEGF8: BS2

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Aug 13, 2019

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

MEGF8-related Carpenter syndrome Benign:1

Jan 15, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

MEGF8-related disorder Benign:1

May 02, 2021

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.078	T
Eigen	Uncertain	0.27
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.84	T
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.0050	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.0	N
PhyloP100		9.1
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-0.50	N
REVEL	Benign	0.091
Sift	Benign	0.12	T
Sift4G	Benign	0.47	T
Polyphen		0.80	P
Vest4		0.13
MVP		0.15
MPC		0.50
ClinPred		0.050	T
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.066
gMVP		0.26
Mutation Taster		=93/7	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: rs147133204; hg19: chr19-42880094; COSMIC: COSV99236736;