rs62648096

Variant names:

• chr19-42360920-C-T
• rs62648096
• NM_001271938.2:c.5634C>T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_001271938.2(MEGF8):​c.5634C>T​(p.Arg1878Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00716 in 1,612,282 control chromosomes in the GnomAD database, including 56 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0065 (6 hom., cov: 32)
  • Exomes 𝑓: 0.0072 (50 hom.)
• Consequence: MEGF8 NM_001271938.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.239
• Publications: 4 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: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P, ClinGen
• Carpenter syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.38).
• BP6: Variant 19-42360920-C-T is Benign according to our data. Variant chr19-42360920-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 473336.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.239 with no splicing effect.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00647 (986/152362) while in subpopulation AMR AF = 0.00738 (113/15310). AF 95% confidence interval is 0.00668. There are 6 homozygotes in GnomAd4. There are 536 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 6 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.5634C>T	p.Arg1878Arg	synonymous	Exon 32 of 42	NP_001258867.1	Q7Z7M0-1
	MEGF8	NM_001410.3		c.5433C>T	p.Arg1811Arg	synonymous	Exon 31 of 41	NP_001401.2	Q7Z7M0-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MEGF8	ENST00000251268.11	TSL:5 MANE Select	c.5634C>T	p.Arg1878Arg	synonymous	Exon 32 of 42	ENSP00000251268.5	Q7Z7M0-1
	MEGF8	ENST00000334370.8	TSL:1	c.5433C>T	p.Arg1811Arg	synonymous	Exon 31 of 41	ENSP00000334219.4	Q7Z7M0-2
	MEGF8	ENST00000378073.5	TSL:5	c.-1452C>T		5_prime_UTR	Exon 32 of 41	ENSP00000367313.4	F5GZG7

Frequencies

GnomAD3 genomes AF: 0.00648 AC: 986 AN: 152244 Hom.: 6 Cov.: 32

Gnomad AFR AF: 0.00169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00739

Gnomad ASJ AF: 0.0233

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00186

Gnomad FIN AF: 0.0191

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.00720

Gnomad OTH AF: 0.00669

GnomAD2 exomes AF: 0.00794 AC: 1957 AN: 246608 AF XY: 0.00812

Gnomad AFR exome AF: 0.00119

Gnomad AMR exome AF: 0.00546

Gnomad ASJ exome AF: 0.0223

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.0165

Gnomad NFE exome AF: 0.00952

Gnomad OTH exome AF: 0.0106

GnomAD4 exome AF: 0.00724 AC: 10566 AN: 1459920 Hom.: 50 Cov.: 32 AF XY: 0.00723 AC XY: 5247 AN XY: 726044

African (AFR) AF: 0.00129 AC: 43 AN: 33458

American (AMR) AF: 0.00592 AC: 264 AN: 44602

Ashkenazi Jewish (ASJ) AF: 0.0238 AC: 619 AN: 26056

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39674

South Asian (SAS) AF: 0.00223 AC: 192 AN: 86094

European-Finnish (FIN) AF: 0.0158 AC: 837 AN: 52936

Middle Eastern (MID) AF: 0.0177 AC: 102 AN: 5754

European-Non Finnish (NFE) AF: 0.00720 AC: 7999 AN: 1111036

Other (OTH) AF: 0.00844 AC: 509 AN: 60310

GnomAD4 genome AF: 0.00647 AC: 986 AN: 152362 Hom.: 6 Cov.: 32 AF XY: 0.00719 AC XY: 536 AN XY: 74500

African (AFR) AF: 0.00168 AC: 70 AN: 41588

American (AMR) AF: 0.00738 AC: 113 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.0233 AC: 81 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5186

South Asian (SAS) AF: 0.00186 AC: 9 AN: 4830

European-Finnish (FIN) AF: 0.0191 AC: 203 AN: 10618

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.00720 AC: 490 AN: 68036

Other (OTH) AF: 0.00662 AC: 14 AN: 2116

Alfa AF: 0.00825 Hom.: 3

Bravo AF: 0.00557

Asia WGS AF: 0.00318 AC: 11 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	MEGF8-related Carpenter syndrome (1)
-	-	1	MEGF8-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.38
CADD	Benign	7.7
DANN	Benign	0.74
PhyloP100		0.24
PromoterAI		0.0035	Neutral
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs62648096; hg19: chr19-42865072; COSMIC: COSV52077410; COSMIC: COSV52077410;