rs755932452

chr19-42357580-C-Achr19-42357580-C-Gchr19-42357580-C-T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2 BP4_Moderate BP6_Moderate BP7

The NM_001271938.2(MEGF8):c.5007C>A(p.Pro1669=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00021 in 1,601,296 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00022 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00021 (0 hom.)
• Consequence: MEGF8 NM_001271938.2 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.219

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 Likely_benign. Variant got -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.28).
• BP6: Variant 19-42357580-C-A is Benign according to our data. Variant chr19-42357580-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 540552.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-0.219 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MEGF8	NM_001271938.2	c.5007C>A	p.Pro1669=	synonymous_variant	28/42	ENST00000251268.11
MEGF8	NM_001410.3	c.4806C>A	p.Pro1602=	synonymous_variant	27/41

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MEGF8	ENST00000251268.11	c.5007C>A	p.Pro1669=	synonymous_variant	28/42	5	NM_001271938.2	A2
MEGF8	ENST00000334370.8	c.4806C>A	p.Pro1602=	synonymous_variant	27/41	1		P2
MEGF8	ENST00000378073.5	c.-2079C>A		5_prime_UTR_variant	28/41	5

Frequencies

GnomAD3 genomes AF: 0.000223 AC: 34 AN: 152154 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00720

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000379 AC: 84 AN: 221386 Hom.: 0 AF XY: 0.000372 AC XY: 45 AN XY: 120878

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000956

Gnomad ASJ exome AF: 0.00709

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000123

Gnomad OTH exome AF: 0.000361

GnomAD4 exome AF: 0.000208 AC: 302 AN: 1449142 Hom.: 0 Cov.: 32 AF XY: 0.000239 AC XY: 172 AN XY: 720084

Gnomad4 AFR exome AF: 0.0000301

Gnomad4 AMR exome AF: 0.0000942

Gnomad4 ASJ exome AF: 0.00739

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000118

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000705

Gnomad4 OTH exome AF: 0.000417

GnomAD4 genome AF: 0.000223 AC: 34 AN: 152154 Hom.: 0 Cov.: 32 AF XY: 0.000135 AC XY: 10 AN XY: 74324

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00720

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000132

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000504 Hom.: 0

Bravo AF: 0.000246

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

MEGF8-related Carpenter syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Mar 06, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.28
Cadd	Benign	1.6
Dann	Benign	0.73

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: rs755932452; hg19: chr19-42861732; COSMIC: COSV104379505; COSMIC: COSV104379505;