rs116630802

Variant names:

• chr19-42359229-G-A
• rs116630802
• NM_001271938.2:c.5475G>A

Your query was ambiguous. Multiple possible variants found:

• chr19-42359229-G-A
• chr19-42359229-G-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.5475G>A​(p.Leu1825Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00585 in 1,577,866 control chromosomes in the GnomAD database, including 421 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.030 (219 hom., cov: 30)
  • Exomes 𝑓: 0.0032 (202 hom.)
• Consequence: MEGF8 NM_001271938.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.767
• 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=-0.45).
• BP6: Variant 19-42359229-G-A is Benign according to our data. Variant chr19-42359229-G-A is described in ClinVar as Benign. ClinVar VariationId is 473335.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.767 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.102 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MEGF8	NM_001271938.2	c.5475G>A	p.Leu1825Leu	synonymous_variant	Exon 31 of 42	ENST00000251268.11	NP_001258867.1
MEGF8	NM_001410.3	c.5274G>A	p.Leu1758Leu	synonymous_variant	Exon 30 of 41		NP_001401.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MEGF8	ENST00000251268.11	c.5475G>A	p.Leu1825Leu	synonymous_variant	Exon 31 of 42	5	NM_001271938.2	ENSP00000251268.5
MEGF8	ENST00000334370.8	c.5274G>A	p.Leu1758Leu	synonymous_variant	Exon 30 of 41	1		ENSP00000334219.4
MEGF8	ENST00000378073.5	c.-1611G>A		5_prime_UTR_variant	Exon 31 of 41	5		ENSP00000367313.4

Frequencies

GnomAD3 genomes AF: 0.0303 AC: 4599 AN: 151978 Hom.: 218 Cov.: 30

Gnomad AFR AF: 0.105

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0115

Gnomad ASJ AF: 0.000289

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.0000943

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000691

Gnomad OTH AF: 0.0187

GnomAD2 exomes AF: 0.00885 AC: 1945 AN: 219754 AF XY: 0.00679

Gnomad AFR exome AF: 0.110

Gnomad AMR exome AF: 0.00680

Gnomad ASJ exome AF: 0.000260

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000598

Gnomad OTH exome AF: 0.00619

GnomAD4 exome AF: 0.00325 AC: 4633 AN: 1425770 Hom.: 202 Cov.: 35 AF XY: 0.00280 AC XY: 1975 AN XY: 706620

African (AFR) AF: 0.106 AC: 3375 AN: 31700

American (AMR) AF: 0.00769 AC: 297 AN: 38600

Ashkenazi Jewish (ASJ) AF: 0.000621 AC: 15 AN: 24172

East Asian (EAS) AF: 0.00 AC: 0 AN: 38814

South Asian (SAS) AF: 0.000413 AC: 34 AN: 82290

European-Finnish (FIN) AF: 0.0000956 AC: 5 AN: 52320

Middle Eastern (MID) AF: 0.00867 AC: 47 AN: 5424

European-Non Finnish (NFE) AF: 0.000357 AC: 391 AN: 1093880

Other (OTH) AF: 0.00801 AC: 469 AN: 58570

GnomAD4 genome AF: 0.0303 AC: 4602 AN: 152096 Hom.: 219 Cov.: 30 AF XY: 0.0293 AC XY: 2176 AN XY: 74362

African (AFR) AF: 0.105 AC: 4336 AN: 41464

American (AMR) AF: 0.0114 AC: 175 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.000289 AC: 1 AN: 3466

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

South Asian (SAS) AF: 0.000415 AC: 2 AN: 4814

European-Finnish (FIN) AF: 0.0000943 AC: 1 AN: 10608

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000691 AC: 47 AN: 67978

Other (OTH) AF: 0.0185 AC: 39 AN: 2112

Alfa AF: 0.0195 Hom.: 62

Bravo AF: 0.0344

Asia WGS AF: 0.00577 AC: 20 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Mar 16, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

MEGF8-related Carpenter syndrome Benign:1

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.45
CADD	Benign	7.0
DANN	Benign	0.71
PhyloP100		0.77
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs116630802; hg19: chr19-42863381; COSMIC: COSV104379235;