NM_001271938.2:c.2299-15_2299-12delTCAC

Variant names:

• chr19-42349479-ATCAC-A
• rs141582110
• NM_001271938.2:c.2299-15_2299-12delTCAC

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_001271938.2(MEGF8):​c.2299-15_2299-12delTCAC variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00469 in 1,604,856 control chromosomes in the GnomAD database, including 46 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0032 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0049 (44 hom.)
• Consequence: MEGF8 NM_001271938.2 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.349
• 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: 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 -16 ACMG points.

• BP6: Variant 19-42349479-ATCAC-A is Benign according to our data. Variant chr19-42349479-ATCAC-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 446027.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00317 (482/152060) while in subpopulation SAS AF = 0.0145 (70/4820). AF 95% confidence interval is 0.0118. There are 2 homozygotes in GnomAd4. There are 258 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MEGF8	NM_001271938.2	MANE Select	c.2299-15_2299-12delTCAC		intron	N/A	NP_001258867.1
	MEGF8	NM_001410.3		c.2098-15_2098-12delTCAC		intron	N/A	NP_001401.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MEGF8	ENST00000251268.11	TSL:5 MANE Select	c.2299-19_2299-16delTCAC		intron	N/A	ENSP00000251268.5
	MEGF8	ENST00000334370.8	TSL:1	c.2098-19_2098-16delTCAC		intron	N/A	ENSP00000334219.4
	MEGF8	ENST00000378073.5	TSL:5	c.-4787-19_-4787-16delTCAC		intron	N/A	ENSP00000367313.4

Frequencies

GnomAD3 genomes AF: 0.00318 AC: 483 AN: 151944 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000629

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00151

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.000387

Gnomad SAS AF: 0.0147

Gnomad FIN AF: 0.00688

Gnomad MID AF: 0.00318

Gnomad NFE AF: 0.00406

Gnomad OTH AF: 0.00478

GnomAD2 exomes AF: 0.00538 AC: 1296 AN: 240788 AF XY: 0.00591

Gnomad AFR exome AF: 0.000515

Gnomad AMR exome AF: 0.00115

Gnomad ASJ exome AF: 0.00114

Gnomad EAS exome AF: 0.0000548

Gnomad FIN exome AF: 0.0103

Gnomad NFE exome AF: 0.00547

Gnomad OTH exome AF: 0.00696

GnomAD4 exome AF: 0.00485 AC: 7050 AN: 1452796 Hom.: 44 AF XY: 0.00522 AC XY: 3766 AN XY: 721830

African (AFR) AF: 0.000661 AC: 22 AN: 33298

American (AMR) AF: 0.00115 AC: 51 AN: 44228

Ashkenazi Jewish (ASJ) AF: 0.000971 AC: 25 AN: 25754

East Asian (EAS) AF: 0.0000506 AC: 2 AN: 39552

South Asian (SAS) AF: 0.0139 AC: 1187 AN: 85696

European-Finnish (FIN) AF: 0.0107 AC: 559 AN: 52004

Middle Eastern (MID) AF: 0.00387 AC: 17 AN: 4388

European-Non Finnish (NFE) AF: 0.00438 AC: 4856 AN: 1108012

Other (OTH) AF: 0.00553 AC: 331 AN: 59864

GnomAD4 genome AF: 0.00317 AC: 482 AN: 152060 Hom.: 2 Cov.: 32 AF XY: 0.00347 AC XY: 258 AN XY: 74336

African (AFR) AF: 0.000627 AC: 26 AN: 41474

American (AMR) AF: 0.00151 AC: 23 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3468

East Asian (EAS) AF: 0.000388 AC: 2 AN: 5158

South Asian (SAS) AF: 0.0145 AC: 70 AN: 4820

European-Finnish (FIN) AF: 0.00688 AC: 73 AN: 10604

Middle Eastern (MID) AF: 0.00342 AC: 1 AN: 292

European-Non Finnish (NFE) AF: 0.00406 AC: 276 AN: 67950

Other (OTH) AF: 0.00473 AC: 10 AN: 2112

Alfa AF: 0.00364 Hom.: 0

Bravo AF: 0.00229

Asia WGS AF: 0.00606 AC: 21 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Oct 29, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Apr 28, 2017

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

MEGF8-related Carpenter syndrome Benign:1

Oct 30, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.35
Mutation Taster		=100/0	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: rs141582110; hg19: chr19-42853631;