chr19-42351693-C-T

Variant names:

• chr19-42351693-C-T
• rs145216125
• NM_001271938.2:c.3033C>T

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS1

The NM_001271938.2(MEGF8):​c.3033C>T​(p.Thr1011Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000367 in 1,594,794 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00057 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00035 (1 hom.)
• Consequence: MEGF8 NM_001271938.2 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.512
• Publications: 0 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 -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.53).
• BP6: Variant 19-42351693-C-T is Benign according to our data. Variant chr19-42351693-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 473324.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.512 with no splicing effect.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000572 (87/152174) while in subpopulation AMR AF = 0.00196 (30/15284). AF 95% confidence interval is 0.00141. There are 0 homozygotes in GnomAd4. There are 55 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

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.3033C>T	p.Thr1011Thr	synonymous	Exon 18 of 42	NP_001258867.1	Q7Z7M0-1
	MEGF8	NM_001410.3		c.2832C>T	p.Thr944Thr	synonymous	Exon 17 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.3033C>T	p.Thr1011Thr	synonymous	Exon 18 of 42	ENSP00000251268.5	Q7Z7M0-1
	MEGF8	ENST00000334370.8	TSL:1	c.2832C>T	p.Thr944Thr	synonymous	Exon 17 of 41	ENSP00000334219.4	Q7Z7M0-2
	MEGF8	ENST00000378073.5	TSL:5	c.-4053C>T		5_prime_UTR_premature_start_codon_gain	Exon 18 of 41	ENSP00000367313.4	F5GZG7

Frequencies

GnomAD3 genomes AF: 0.000572 AC: 87 AN: 152174 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00196

Gnomad ASJ AF: 0.0109

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000221

Gnomad OTH AF: 0.000958

GnomAD2 exomes AF: 0.000582 AC: 128 AN: 220066 AF XY: 0.000649

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000513

Gnomad ASJ exome AF: 0.00802

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000326

Gnomad OTH exome AF: 0.000361

GnomAD4 exome AF: 0.000346 AC: 499 AN: 1442620 Hom.: 1 Cov.: 32 AF XY: 0.000362 AC XY: 259 AN XY: 715812

African (AFR) AF: 0.000151 AC: 5 AN: 33044

American (AMR) AF: 0.000358 AC: 15 AN: 41864

Ashkenazi Jewish (ASJ) AF: 0.00924 AC: 238 AN: 25746

East Asian (EAS) AF: 0.00 AC: 0 AN: 38548

South Asian (SAS) AF: 0.0000241 AC: 2 AN: 82822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51930

Middle Eastern (MID) AF: 0.000870 AC: 5 AN: 5748

European-Non Finnish (NFE) AF: 0.000158 AC: 174 AN: 1103270

Other (OTH) AF: 0.00101 AC: 60 AN: 59648

GnomAD4 genome AF: 0.000572 AC: 87 AN: 152174 Hom.: 0 Cov.: 33 AF XY: 0.000740 AC XY: 55 AN XY: 74320

African (AFR) AF: 0.0000482 AC: 2 AN: 41452

American (AMR) AF: 0.00196 AC: 30 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.0109 AC: 38 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000221 AC: 15 AN: 68018

Other (OTH) AF: 0.000958 AC: 2 AN: 2088

Alfa AF: 0.00114 Hom.: 0

Bravo AF: 0.000548

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.53
CADD	Benign	5.0
DANN	Benign	0.36
PhyloP100		-0.51
Mutation Taster		=91/9	polymorphism

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

Other links and lift over

dbSNP: rs145216125; hg19: chr19-42855845;