rs138235390

Variant names:

• chr19-42370784-C-T
• rs138235390
• NM_001271938.2:c.7089C>T

Your query was ambiguous. Multiple possible variants found:

• chr19-42370784-C-T
• chr19-42370784-C-A
• chr19-42370784-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.7089C>T​(p.Cys2363Cys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000395 in 1,512,866 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 0.00033 (0 hom., cov: 25)
  • Exomes 𝑓: 0.00040 (1 hom.)
• Consequence: MEGF8 NM_001271938.2 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.453
• 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_addAF=-0.340325).
• BP6: Variant 19-42370784-C-T is Benign according to our data. Variant chr19-42370784-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 473344.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.453 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000334 (47/140668) while in subpopulation NFE AF = 0.000576 (38/65992). AF 95% confidence interval is 0.000431. There are 0 homozygotes in GnomAd4. There are 26 alleles in the male GnomAd4 subpopulation. Median coverage is 25. 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.7089C>T	p.Cys2363Cys	synonymous	Exon 40 of 42	NP_001258867.1	Q7Z7M0-1
	MEGF8	NM_001410.3		c.6888C>T	p.Cys2296Cys	synonymous	Exon 39 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.7089C>T	p.Cys2363Cys	synonymous	Exon 40 of 42	ENSP00000251268.5	Q7Z7M0-1
	MEGF8	ENST00000334370.8	TSL:1	c.6888C>T	p.Cys2296Cys	synonymous	Exon 39 of 41	ENSP00000334219.4	Q7Z7M0-2
	MEGF8	ENST00000593647.1	TSL:1	c.348C>T	p.Cys116Cys	synonymous	Exon 3 of 4	ENSP00000470620.1	M0QZL2

Frequencies

GnomAD3 genomes AF: 0.000334 AC: 47 AN: 140668 Hom.: 0 Cov.: 25

Gnomad AFR AF: 0.000159

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000159

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000224

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000576

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000374 AC: 63 AN: 168552 AF XY: 0.000304

Gnomad AFR exome AF: 0.000206

Gnomad AMR exome AF: 0.000198

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000725

Gnomad OTH exome AF: 0.000643

GnomAD4 exome AF: 0.000401 AC: 550 AN: 1372198 Hom.: 1 Cov.: 25 AF XY: 0.000387 AC XY: 263 AN XY: 679498

African (AFR) AF: 0.0000319 AC: 1 AN: 31376

American (AMR) AF: 0.000192 AC: 7 AN: 36410

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24990

East Asian (EAS) AF: 0.00 AC: 0 AN: 36230

South Asian (SAS) AF: 0.000379 AC: 30 AN: 79140

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49770

Middle Eastern (MID) AF: 0.000358 AC: 2 AN: 5594

European-Non Finnish (NFE) AF: 0.000472 AC: 496 AN: 1051520

Other (OTH) AF: 0.000245 AC: 14 AN: 57168

GnomAD4 genome AF: 0.000334 AC: 47 AN: 140668 Hom.: 0 Cov.: 25 AF XY: 0.000385 AC XY: 26 AN XY: 67454

African (AFR) AF: 0.000159 AC: 6 AN: 37804

American (AMR) AF: 0.000159 AC: 2 AN: 12560

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3410

East Asian (EAS) AF: 0.00 AC: 0 AN: 4796

South Asian (SAS) AF: 0.000224 AC: 1 AN: 4474

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8576

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 266

European-Non Finnish (NFE) AF: 0.000576 AC: 38 AN: 65992

Other (OTH) AF: 0.00 AC: 0 AN: 1904

Alfa AF: 0.000314 Hom.: 0

Bravo AF: 0.000332

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000815 AC: 7

ExAC AF: 0.000202 AC: 23

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_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	6.7
DANN	Uncertain	1.0
Eigen	Benign	-0.51
Eigen_PC	Benign	-0.54
FATHMM_MKL	Benign	0.15	N
PhyloP100		-0.45
Vest4		0.34
GERP RS		-1.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=87/113	disease causing

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

Other links and lift over

dbSNP: rs138235390; hg19: chr19-42874936; COSMIC: COSV99237755;