19-42368446-C-G

Variant names:

• chr19-42368446-C-G
• rs373417416
• NM_001271938.2:c.6274-9C>G

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001271938.2(MEGF8):​c.6274-9C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000411 in 1,595,510 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00065 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00039 (2 hom.)
• Consequence: MEGF8 NM_001271938.2 intron
• Scores: Splicing: ADA: 0.001318
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: -0.103
• Publications: 1 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 19-42368446-C-G is Benign according to our data. Variant chr19-42368446-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 435857.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00065 (99/152344) while in subpopulation AFR AF = 0.00115 (48/41586). AF 95% confidence interval is 0.000894. There are 1 homozygotes in GnomAd4. There are 58 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 2 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001271938.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MEGF8	NM_001271938.2	MANE Select	c.6274-9C>G		intron	N/A	NP_001258867.1
	MEGF8	NM_001410.3		c.6073-9C>G		intron	N/A	NP_001401.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MEGF8	ENST00000251268.11	TSL:5 MANE Select	c.6274-9C>G		intron	N/A	ENSP00000251268.5
	MEGF8	ENST00000334370.8	TSL:1	c.6073-9C>G		intron	N/A	ENSP00000334219.4
	MEGF8	ENST00000378073.5	TSL:5	c.-812-9C>G		intron	N/A	ENSP00000367313.4

Frequencies

GnomAD3 genomes AF: 0.000650 AC: 99 AN: 152226 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00116

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000850

Gnomad ASJ AF: 0.00317

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.000279

Gnomad OTH AF: 0.000957

GnomAD2 exomes AF: 0.000506 AC: 113 AN: 223438 AF XY: 0.000586

Gnomad AFR exome AF: 0.00101

Gnomad AMR exome AF: 0.000473

Gnomad ASJ exome AF: 0.00201

Gnomad EAS exome AF: 0.000407

Gnomad FIN exome AF: 0.0000487

Gnomad NFE exome AF: 0.000444

Gnomad OTH exome AF: 0.000902

GnomAD4 exome AF: 0.000385 AC: 556 AN: 1443166 Hom.: 2 Cov.: 31 AF XY: 0.000414 AC XY: 297 AN XY: 716862

African (AFR) AF: 0.00131 AC: 43 AN: 32826

American (AMR) AF: 0.000474 AC: 20 AN: 42192

Ashkenazi Jewish (ASJ) AF: 0.00213 AC: 54 AN: 25344

East Asian (EAS) AF: 0.000332 AC: 13 AN: 39194

South Asian (SAS) AF: 0.000360 AC: 30 AN: 83404

European-Finnish (FIN) AF: 0.0000776 AC: 4 AN: 51528

Middle Eastern (MID) AF: 0.00841 AC: 48 AN: 5708

European-Non Finnish (NFE) AF: 0.000271 AC: 299 AN: 1103388

Other (OTH) AF: 0.000755 AC: 45 AN: 59582

GnomAD4 genome AF: 0.000650 AC: 99 AN: 152344 Hom.: 1 Cov.: 32 AF XY: 0.000779 AC XY: 58 AN XY: 74490

African (AFR) AF: 0.00115 AC: 48 AN: 41586

American (AMR) AF: 0.000849 AC: 13 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00317 AC: 11 AN: 3468

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.000279 AC: 19 AN: 68028

Other (OTH) AF: 0.000947 AC: 2 AN: 2112

Alfa AF: 0.000701 Hom.: 0

Bravo AF: 0.000676

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	1	MEGF8-related Carpenter syndrome (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.28
DANN	Benign	0.38
PhyloP100		-0.10
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0013
dbscSNV1_RF	Benign	0.050
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: rs373417416; hg19: chr19-42872598;