rs150535071

chr19-42344554-C-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.1902C>T(p.Cys634=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00174 in 1,599,034 control chromosomes in the GnomAD database, including 42 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0090 (20 hom., cov: 32)
  • Exomes 𝑓: 0.00097 (22 hom.)
• Consequence: MEGF8 NM_001271938.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.70

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=-0.45).
• BP6: Variant 19-42344554-C-T is Benign according to our data. Variant chr19-42344554-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 540548.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-42344554-C-T is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-1.7 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00903 (1375/152232) while in subpopulation AFR AF= 0.0312 (1298/41548). AF 95% confidence interval is 0.0298. There are 20 homozygotes in gnomad4. There are 620 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 20 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MEGF8	NM_001271938.2	c.1902C>T	p.Cys634=	synonymous_variant	11/42	ENST00000251268.11
MEGF8	NM_001410.3	c.1902C>T	p.Cys634=	synonymous_variant	11/41

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MEGF8	ENST00000251268.11	c.1902C>T	p.Cys634=	synonymous_variant	11/42	5	NM_001271938.2	A2
MEGF8	ENST00000334370.8	c.1902C>T	p.Cys634=	synonymous_variant	11/41	1		P2
MEGF8	ENST00000378073.5	c.-5184C>T		5_prime_UTR_variant	11/41	5

Frequencies

GnomAD3 genomes AF: 0.00899 AC: 1368 AN: 152114 Hom.: 20 Cov.: 32

Gnomad AFR AF: 0.0312

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00393

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00622

GnomAD3 exomes AF: 0.00238 AC: 550 AN: 230950 Hom.: 12 AF XY: 0.00175 AC XY: 221 AN XY: 126512

Gnomad AFR exome AF: 0.0314

Gnomad AMR exome AF: 0.00163

Gnomad ASJ exome AF: 0.000310

Gnomad EAS exome AF: 0.0000562

Gnomad SAS exome AF: 0.0000332

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000114

Gnomad OTH exome AF: 0.00139

GnomAD4 exome AF: 0.000971 AC: 1405 AN: 1446802 Hom.: 22 Cov.: 31 AF XY: 0.000851 AC XY: 613 AN XY: 719946

Gnomad4 AFR exome AF: 0.0334

Gnomad4 AMR exome AF: 0.00201

Gnomad4 ASJ exome AF: 0.000154

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000815

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000478

Gnomad4 OTH exome AF: 0.00212

GnomAD4 genome AF: 0.00903 AC: 1375 AN: 152232 Hom.: 20 Cov.: 32 AF XY: 0.00833 AC XY: 620 AN XY: 74434

Gnomad4 AFR AF: 0.0312

Gnomad4 AMR AF: 0.00392

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00616

Alfa AF: 0.00283 Hom.: 1

Bravo AF: 0.0106

Asia WGS AF: 0.00173 AC: 6 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 26, 2023

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

May 05, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.45
Cadd	Benign	0.54
Dann	Benign	0.50
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs150535071; hg19: chr19-42848706; COSMIC: COSV104379416;