rs779853780

Positions:

• chr19-42363053-A-C
• chr19-42363053-A-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_001271938.2(MEGF8):​c.6064A>C​(p.Thr2022Pro) variant causes a missense change. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T2022A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000041 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: MEGF8 NM_001271938.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.07

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 -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.15899652).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MEGF8	NM_001271938.2	c.6064A>C	p.Thr2022Pro	missense_variant	35/42	ENST00000251268.11
MEGF8	NM_001410.3	c.5863A>C	p.Thr1955Pro	missense_variant	34/41

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MEGF8	ENST00000251268.11	c.6064A>C	p.Thr2022Pro	missense_variant	35/42	5	NM_001271938.2	A2
MEGF8	ENST00000334370.8	c.5863A>C	p.Thr1955Pro	missense_variant	34/41	1		P2
MEGF8	ENST00000378073.5	c.-1022A>C		5_prime_UTR_variant	35/41	5
MEGF8	ENST00000598762.1	c.161+840A>C		intron_variant		3

Frequencies

GnomAD3 genomes AF: 0.00 AC: 4 AN: 150870 Hom.: 0 Cov.: 32 FAILED QC

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000594

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000407 AC: 59 AN: 1450992 Hom.: 0 Cov.: 33 AF XY: 0.0000430 AC XY: 31 AN XY: 721076

Gnomad4 AFR exome AF: 0.0000301

Gnomad4 AMR exome AF: 0.000162

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000154

Gnomad4 SAS exome AF: 0.0000353

Gnomad4 FIN exome AF: 0.000580

Gnomad4 NFE exome AF: 0.00000903

Gnomad4 OTH exome AF: 0.0000334

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000331 AC: 5 AN: 150970 Hom.: 0 Cov.: 32 AF XY: 0.0000543 AC XY: 4 AN XY: 73638

Gnomad4 AFR AF: 0.0000242

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000594

Gnomad4 OTH AF: 0.00

ExAC AF: 0.000255 AC: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Benign	-0.093	T
BayesDel_noAF	Benign	-0.37
CADD	Uncertain	24
DANN	Uncertain	0.99
Eigen	Uncertain	0.43
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.85	D;D
M_CAP	Benign	0.038	D
MetaRNN	Benign	0.16	T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.77	T
PROVEAN	Uncertain	-2.5	D;D
REVEL	Benign	0.17
Sift	Benign	0.060	T;D
Sift4G	Uncertain	0.013	D;D
Polyphen		0.99	D;P
Vest4		0.40
MVP		0.12
MPC		1.6
ClinPred		0.066	T
GERP RS		5.1
Varity_R		0.47
gMVP		0.72

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: rs779853780; hg19: chr19-42867205;