rs149190709

Variant names:

• chr19-42336299-C-T
• rs149190709
• NM_001271938.2:c.1197C>T

Your query was ambiguous. Multiple possible variants found:

• chr19-42336299-C-T
• chr19-42336299-C-A
• chr19-42336299-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.1197C>T​(p.Pro399Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00941 in 1,607,412 control chromosomes in the GnomAD database, including 95 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0073 (9 hom., cov: 33)
  • Exomes 𝑓: 0.0096 (86 hom.)
• Consequence: MEGF8 NM_001271938.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -7.01
• Publications: 3 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=-0.98).
• BP6: Variant 19-42336299-C-T is Benign according to our data. Variant chr19-42336299-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 473322.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-7.01 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00733 (1117/152360) while in subpopulation NFE AF = 0.0101 (688/68030). AF 95% confidence interval is 0.00949. There are 9 homozygotes in GnomAd4. There are 598 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 9 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.1197C>T	p.Pro399Pro	synonymous	Exon 6 of 42	NP_001258867.1	Q7Z7M0-1
	MEGF8	NM_001410.3		c.1197C>T	p.Pro399Pro	synonymous	Exon 6 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.1197C>T	p.Pro399Pro	synonymous	Exon 6 of 42	ENSP00000251268.5	Q7Z7M0-1
	MEGF8	ENST00000334370.8	TSL:1	c.1197C>T	p.Pro399Pro	synonymous	Exon 6 of 41	ENSP00000334219.4	Q7Z7M0-2
	MEGF8	ENST00000378073.5	TSL:5	c.-5889C>T		5_prime_UTR	Exon 6 of 41	ENSP00000367313.4	F5GZG7

Frequencies

GnomAD3 genomes AF: 0.00734 AC: 1118 AN: 152242 Hom.: 9 Cov.: 33

Gnomad AFR AF: 0.00154

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00425

Gnomad ASJ AF: 0.0101

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00621

Gnomad FIN AF: 0.0205

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.0101

Gnomad OTH AF: 0.00621

GnomAD2 exomes AF: 0.00796 AC: 1939 AN: 243656 AF XY: 0.00836

Gnomad AFR exome AF: 0.00150

Gnomad AMR exome AF: 0.00445

Gnomad ASJ exome AF: 0.00987

Gnomad EAS exome AF: 0.0000557

Gnomad FIN exome AF: 0.0188

Gnomad NFE exome AF: 0.00939

Gnomad OTH exome AF: 0.00787

GnomAD4 exome AF: 0.00962 AC: 14002 AN: 1455052 Hom.: 86 Cov.: 32 AF XY: 0.00971 AC XY: 7032 AN XY: 723910

African (AFR) AF: 0.00114 AC: 38 AN: 33458

American (AMR) AF: 0.00517 AC: 231 AN: 44656

Ashkenazi Jewish (ASJ) AF: 0.00975 AC: 254 AN: 26062

East Asian (EAS) AF: 0.00 AC: 0 AN: 39664

South Asian (SAS) AF: 0.00800 AC: 689 AN: 86100

European-Finnish (FIN) AF: 0.0187 AC: 894 AN: 47916

Middle Eastern (MID) AF: 0.0149 AC: 86 AN: 5760

European-Non Finnish (NFE) AF: 0.0102 AC: 11299 AN: 1111146

Other (OTH) AF: 0.00848 AC: 511 AN: 60290

GnomAD4 genome AF: 0.00733 AC: 1117 AN: 152360 Hom.: 9 Cov.: 33 AF XY: 0.00803 AC XY: 598 AN XY: 74508

African (AFR) AF: 0.00154 AC: 64 AN: 41588

American (AMR) AF: 0.00425 AC: 65 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.0101 AC: 35 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00600 AC: 29 AN: 4830

European-Finnish (FIN) AF: 0.0205 AC: 218 AN: 10624

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.0101 AC: 688 AN: 68030

Other (OTH) AF: 0.00615 AC: 13 AN: 2114

Alfa AF: 0.00674 Hom.: 1

Bravo AF: 0.00580

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.0119

EpiControl AF: 0.0103

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	MEGF8-related Carpenter syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.98
CADD	Benign	0.86
DANN	Benign	0.52
PhyloP100		-7.0
Mutation Taster		=88/12	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: rs149190709; hg19: chr19-42840451; COSMIC: COSV99235285;