rs62648096

Variant names:

• chr19-42360920-C-T
• rs62648096
• NM_001271938.2:c.5634C>T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_001271938.2(MEGF8):​c.5634C>T​(p.Arg1878Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00716 in 1,612,282 control chromosomes in the GnomAD database, including 56 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0065 (6 hom., cov: 32)
  • Exomes 𝑓: 0.0072 (50 hom.)
• Consequence: MEGF8 NM_001271938.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.239

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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.38).
• BP6: Variant 19-42360920-C-T is Benign according to our data. Variant chr19-42360920-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 473336.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.239 with no splicing effect.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00647 (986/152362) while in subpopulation AMR AF= 0.00738 (113/15310). AF 95% confidence interval is 0.00668. There are 6 homozygotes in gnomad4. There are 536 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MEGF8	NM_001271938.2	c.5634C>T	p.Arg1878Arg	synonymous_variant	Exon 32 of 42	ENST00000251268.11	NP_001258867.1
MEGF8	NM_001410.3	c.5433C>T	p.Arg1811Arg	synonymous_variant	Exon 31 of 41		NP_001401.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MEGF8	ENST00000251268.11	c.5634C>T	p.Arg1878Arg	synonymous_variant	Exon 32 of 42	5	NM_001271938.2	ENSP00000251268.5
MEGF8	ENST00000334370.8	c.5433C>T	p.Arg1811Arg	synonymous_variant	Exon 31 of 41	1		ENSP00000334219.4
MEGF8	ENST00000378073	c.-1452C>T		5_prime_UTR_variant	Exon 32 of 41	5		ENSP00000367313.4
MEGF8	ENST00000598762.1	c.-52C>T		upstream_gene_variant		3		ENSP00000471370.1

Frequencies

GnomAD3 genomes AF: 0.00648 AC: 986 AN: 152244 Hom.: 6 Cov.: 32

Gnomad AFR AF: 0.00169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00739

Gnomad ASJ AF: 0.0233

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00186

Gnomad FIN AF: 0.0191

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.00720

Gnomad OTH AF: 0.00669

GnomAD3 exomes AF: 0.00794 AC: 1957 AN: 246608 Hom.: 13 AF XY: 0.00812 AC XY: 1086 AN XY: 133736

Gnomad AFR exome AF: 0.00119

Gnomad AMR exome AF: 0.00546

Gnomad ASJ exome AF: 0.0223

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00210

Gnomad FIN exome AF: 0.0165

Gnomad NFE exome AF: 0.00952

Gnomad OTH exome AF: 0.0106

GnomAD4 exome AF: 0.00724 AC: 10566 AN: 1459920 Hom.: 50 Cov.: 32 AF XY: 0.00723 AC XY: 5247 AN XY: 726044

Gnomad4 AFR exome AF: 0.00129

Gnomad4 AMR exome AF: 0.00592

Gnomad4 ASJ exome AF: 0.0238

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00223

Gnomad4 FIN exome AF: 0.0158

Gnomad4 NFE exome AF: 0.00720

Gnomad4 OTH exome AF: 0.00844

GnomAD4 genome AF: 0.00647 AC: 986 AN: 152362 Hom.: 6 Cov.: 32 AF XY: 0.00719 AC XY: 536 AN XY: 74500

Gnomad4 AFR AF: 0.00168

Gnomad4 AMR AF: 0.00738

Gnomad4 ASJ AF: 0.0233

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00186

Gnomad4 FIN AF: 0.0191

Gnomad4 NFE AF: 0.00720

Gnomad4 OTH AF: 0.00662

Alfa AF: 0.00825 Hom.: 3

Bravo AF: 0.00557

Asia WGS AF: 0.00318 AC: 11 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Nov 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

MEGF8: BP4, BP7, BS2 -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Mar 31, 2021

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

MEGF8-related Carpenter syndrome Benign:1

Jan 28, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

MEGF8-related disorder Benign:1

Jan 19, 2023

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 v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.38
CADD	Benign	7.7
DANN	Benign	0.74

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

Publications

LitVar

Other links and lift over

dbSNP: rs62648096; hg19: chr19-42865072; COSMIC: COSV52077410; COSMIC: COSV52077410;