rs117439608

chr19-42334057-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Moderate BP6_Moderate BP7 BS1 BS2

The NM_001271938.2(MEGF8):c.402C>T(p.Asn134=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000944 in 1,613,840 control chromosomes in the GnomAD database, including 18 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.00077 (2 hom., cov: 32)
  • Exomes 𝑓: 0.00096 (16 hom.)
• Consequence: MEGF8 NM_001271938.2 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.761

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.43).
• BP6: Variant 19-42334057-C-T is Benign according to our data. Variant chr19-42334057-C-T is described in ClinVar as [Benign]. Clinvar id is 540551.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-0.761 with no splicing effect.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000768 (117/152312) while in subpopulation EAS AF= 0.0195 (101/5176). AF 95% confidence interval is 0.0164. There are 2 homozygotes in gnomad4. There are 63 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MEGF8	NM_001271938.2	c.402C>T	p.Asn134=	synonymous_variant	3/42	ENST00000251268.11
MEGF8	NM_001410.3	c.402C>T	p.Asn134=	synonymous_variant	3/41

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MEGF8	ENST00000251268.11	c.402C>T	p.Asn134=	synonymous_variant	3/42	5	NM_001271938.2	A2
MEGF8	ENST00000334370.8	c.402C>T	p.Asn134=	synonymous_variant	3/41	1		P2
MEGF8	ENST00000378073.5	c.-6684C>T		5_prime_UTR_variant	3/41	5

Frequencies

GnomAD3 genomes AF: 0.000769 AC: 117 AN: 152194 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000193

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0195

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.00115 AC: 287 AN: 248614 Hom.: 2 AF XY: 0.000948 AC XY: 128 AN XY: 134952

Gnomad AFR exome AF: 0.000130

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0151

Gnomad SAS exome AF: 0.000131

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000621

Gnomad OTH exome AF: 0.000497

GnomAD4 exome AF: 0.000963 AC: 1407 AN: 1461528 Hom.: 16 Cov.: 31 AF XY: 0.000912 AC XY: 663 AN XY: 727050

Gnomad4 AFR exome AF: 0.000209

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0318

Gnomad4 SAS exome AF: 0.000209

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000773

Gnomad4 OTH exome AF: 0.000514

GnomAD4 genome AF: 0.000768 AC: 117 AN: 152312 Hom.: 2 Cov.: 32 AF XY: 0.000846 AC XY: 63 AN XY: 74468

Gnomad4 AFR AF: 0.000192

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0195

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000882

Gnomad4 OTH AF: 0.000474

Alfa AF: 0.0000893 Hom.: 0

Bravo AF: 0.000676

Asia WGS AF: 0.00837 AC: 29 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.00

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

MEGF8-related Carpenter syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jun 06, 2023

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.43
Cadd	Benign	1.8
Dann	Benign	0.60

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs117439608; hg19: chr19-42838209; COSMIC: COSV52086761;