rs755400663

Variant names:

• chr19-42376508-C-T
• rs755400663
• NM_001271938.2:c.8271C>T

Your query was ambiguous. Multiple possible variants found:

• chr19-42376508-C-T
• chr19-42376508-C-G

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.8271C>T​(p.Pro2757Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000205 in 1,582,750 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00038 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00019 (0 hom.)
• Consequence: MEGF8 NM_001271938.2 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.08
• 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: 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=-0.77).
• BP6: Variant 19-42376508-C-T is Benign according to our data. Variant chr19-42376508-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 540555.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.08 with no splicing effect.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000381 (58/152338) while in subpopulation AMR AF = 0.00157 (24/15314). AF 95% confidence interval is 0.00108. There are 0 homozygotes in GnomAd4. There are 15 alleles in the male GnomAd4 subpopulation. Median coverage is 32. 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.8271C>T	p.Pro2757Pro	synonymous	Exon 42 of 42	NP_001258867.1	Q7Z7M0-1
	MEGF8	NM_001410.3		c.8070C>T	p.Pro2690Pro	synonymous	Exon 41 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.8271C>T	p.Pro2757Pro	synonymous	Exon 42 of 42	ENSP00000251268.5	Q7Z7M0-1
	MEGF8	ENST00000334370.8	TSL:1	c.8070C>T	p.Pro2690Pro	synonymous	Exon 41 of 41	ENSP00000334219.4	Q7Z7M0-2
	MEGF8	ENST00000593647.1	TSL:1	c.*860C>T		3_prime_UTR	Exon 4 of 4	ENSP00000470620.1	M0QZL2

Frequencies

GnomAD3 genomes AF: 0.000342 AC: 52 AN: 152220 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00157

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00116

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000162

Gnomad OTH AF: 0.00144

GnomAD2 exomes AF: 0.000163 AC: 31 AN: 190374 AF XY: 0.000124

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000140

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000365

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000195

Gnomad OTH exome AF: 0.000802

GnomAD4 exome AF: 0.000186 AC: 266 AN: 1430412 Hom.: 0 Cov.: 31 AF XY: 0.000170 AC XY: 121 AN XY: 709800

African (AFR) AF: 0.00 AC: 0 AN: 32562

American (AMR) AF: 0.000226 AC: 9 AN: 39834

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25536

East Asian (EAS) AF: 0.000400 AC: 15 AN: 37500

South Asian (SAS) AF: 0.0000241 AC: 2 AN: 82986

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47426

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5726

European-Non Finnish (NFE) AF: 0.000166 AC: 182 AN: 1099584

Other (OTH) AF: 0.000979 AC: 58 AN: 59258

GnomAD4 genome AF: 0.000381 AC: 58 AN: 152338 Hom.: 0 Cov.: 32 AF XY: 0.000201 AC XY: 15 AN XY: 74490

African (AFR) AF: 0.000168 AC: 7 AN: 41572

American (AMR) AF: 0.00157 AC: 24 AN: 15314

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00116 AC: 6 AN: 5176

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000162 AC: 11 AN: 68034

Other (OTH) AF: 0.00426 AC: 9 AN: 2112

Alfa AF: 0.000180 Hom.: 0

Bravo AF: 0.000257

Asia WGS AF: 0.0160 AC: 57 AN: 3478

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	-0.77
CADD	Benign	3.4
DANN	Benign	0.51
PhyloP100		-1.1

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: rs755400663; hg19: chr19-42880660; COSMIC: COSV99235344; COSMIC: COSV99235344;