rs145886667

Variant names:

• chr19-42370736-C-T
• rs145886667
• NM_001271938.2:c.7041C>T

Your query was ambiguous. Multiple possible variants found:

• chr19-42370736-C-T
• chr19-42370736-C-G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001271938.2(MEGF8):​c.7041C>T​(p.Asp2347Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0021 in 1,588,454 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0017 (0 hom., cov: 27)
  • Exomes 𝑓: 0.0021 (8 hom.)
• Consequence: MEGF8 NM_001271938.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -2.75
• 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.55).
• BP6: Variant 19-42370736-C-T is Benign according to our data. Variant chr19-42370736-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 473341.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.75 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00172 (260/151206) while in subpopulation NFE AF = 0.00167 (113/67780). AF 95% confidence interval is 0.00142. There are 0 homozygotes in GnomAd4. There are 147 alleles in the male GnomAd4 subpopulation. Median coverage is 27. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 8 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.7041C>T	p.Asp2347Asp	synonymous	Exon 40 of 42	NP_001258867.1	Q7Z7M0-1
	MEGF8	NM_001410.3		c.6840C>T	p.Asp2280Asp	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.7041C>T	p.Asp2347Asp	synonymous	Exon 40 of 42	ENSP00000251268.5	Q7Z7M0-1
	MEGF8	ENST00000334370.8	TSL:1	c.6840C>T	p.Asp2280Asp	synonymous	Exon 39 of 41	ENSP00000334219.4	Q7Z7M0-2
	MEGF8	ENST00000593647.1	TSL:1	c.300C>T	p.Asp100Asp	synonymous	Exon 3 of 4	ENSP00000470620.1	M0QZL2

Frequencies

GnomAD3 genomes AF: 0.00172 AC: 260 AN: 151088 Hom.: 0 Cov.: 27

Gnomad AFR AF: 0.000267

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000597

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000419

Gnomad FIN AF: 0.0118

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00167

Gnomad OTH AF: 0.000484

GnomAD2 exomes AF: 0.00219 AC: 465 AN: 212192 AF XY: 0.00236

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000300

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000634

Gnomad FIN exome AF: 0.0114

Gnomad NFE exome AF: 0.00177

Gnomad OTH exome AF: 0.00275

GnomAD4 exome AF: 0.00213 AC: 3068 AN: 1437248 Hom.: 8 Cov.: 32 AF XY: 0.00217 AC XY: 1549 AN XY: 712422

African (AFR) AF: 0.000212 AC: 7 AN: 33004

American (AMR) AF: 0.000416 AC: 17 AN: 40826

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25656

East Asian (EAS) AF: 0.0000777 AC: 3 AN: 38618

South Asian (SAS) AF: 0.00182 AC: 150 AN: 82228

European-Finnish (FIN) AF: 0.00968 AC: 501 AN: 51750

Middle Eastern (MID) AF: 0.00331 AC: 19 AN: 5736

European-Non Finnish (NFE) AF: 0.00204 AC: 2248 AN: 1099844

Other (OTH) AF: 0.00206 AC: 123 AN: 59586

GnomAD4 genome AF: 0.00172 AC: 260 AN: 151206 Hom.: 0 Cov.: 27 AF XY: 0.00199 AC XY: 147 AN XY: 73790

African (AFR) AF: 0.000267 AC: 11 AN: 41268

American (AMR) AF: 0.000596 AC: 9 AN: 15104

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3462

East Asian (EAS) AF: 0.00 AC: 0 AN: 5118

South Asian (SAS) AF: 0.000420 AC: 2 AN: 4764

European-Finnish (FIN) AF: 0.0118 AC: 123 AN: 10422

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00167 AC: 113 AN: 67780

Other (OTH) AF: 0.000479 AC: 1 AN: 2086

Alfa AF: 0.00148 Hom.: 0

Bravo AF: 0.000903

Asia WGS AF: 0.000289 AC: 1 AN: 3476

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	MEGF8-related Carpenter syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.55
CADD	Benign	0.054
DANN	Benign	0.89
PhyloP100		-2.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=94/6	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: rs145886667; hg19: chr19-42874888;