2-46905517-G-C

Variant names:

• chr2-46905517-G-C
• rs137852913
• NM_139279.6:c.387C>G

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PM1 PM2 PP3_Strong PP5

The NM_139279.6(MCFD2):​c.387C>G​(p.Asp129Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 31)
• Consequence: MCFD2 NM_139279.6 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 2.63
• Publications: 8 publications found

Genes affected

MCFD2 (HGNC:18451): (multiple coagulation factor deficiency 2, ER cargo receptor complex subunit) This gene encodes a soluble luminal protein with two calmodulin-like EF-hand motifs at its C-terminus. This protein forms a complex with LMAN1 (lectin mannose binding protein 1; also known as ERGIC-53) that facilitates the transport of coagulation factors V (FV) and VIII (FVIII) from the endoplasmic reticulum to the Golgi apparatus via an endoplasmic reticulum Golgi intermediate compartment (ERGIC). Mutations in this gene cause combined deficiency of FV and FVIII (F5F8D); a rare autosomal recessive bleeding disorder characterized by mild to moderate bleeding and coordinate reduction in plasma FV and FVIII levels. This protein has also been shown to maintain stem cell potential in adult central nervous system and is a marker for testicular germ cell tumors. The 3' UTR of this gene contains a transposon-like human repeat element named 'THE 1'. A processed RNA pseudogene of this gene is on chromosome 6p22.1. Alternative splicing results in multiple transcript variants encoding distinct isoforms. [provided by RefSeq, Apr 2016]

ENSG00000228925 (HGNC:58223):

LINC01118 (HGNC:49261): (long intergenic non-protein coding RNA 1118)

ACMG classification

Our verdict: Likely_pathogenic. The variant received 9 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_139279.6
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.982
• PP5: Variant 2-46905517-G-C is Pathogenic according to our data. Variant chr2-46905517-G-C is described in ClinVar as Pathogenic. ClinVar VariationId is 2870.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_139279.6. 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
	MCFD2	NM_139279.6	MANE Select	c.387C>G	p.Asp129Glu	missense	Exon 4 of 4	NP_644808.1
	MCFD2	NM_001171506.2		c.387C>G	p.Asp129Glu	missense	Exon 5 of 5	NP_001164977.1
	MCFD2	NM_001171507.2		c.387C>G	p.Asp129Glu	missense	Exon 4 of 4	NP_001164978.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MCFD2	ENST00000319466.9	TSL:1 MANE Select	c.387C>G	p.Asp129Glu	missense	Exon 4 of 4	ENSP00000317271.4
	MCFD2	ENST00000409913.5	TSL:1	c.231C>G	p.Asp77Glu	missense	Exon 3 of 3	ENSP00000386941.1
	MCFD2	ENST00000409105.5	TSL:5	c.387C>G	p.Asp129Glu	missense	Exon 5 of 5	ENSP00000386651.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Factor 5 and Factor VIII, combined deficiency of, 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.55	D
BayesDel_noAF	Pathogenic	0.55
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.83	D
Eigen	Uncertain	0.67
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.96	D
M_CAP	Pathogenic	0.74	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.3	H
PhyloP100		2.6
PrimateAI	Uncertain	0.79	T
PROVEAN	Uncertain	-3.8	D
REVEL	Pathogenic	0.93
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.86
MutPred		0.91		Loss of ubiquitination at K130 (P = 0.0931)
MVP		0.98
MPC		0.19
ClinPred		1.0	D
GERP RS		2.7
Varity_R		0.99
gMVP		0.90
Mutation Taster		=0/100	disease causing (ClinVar)

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: rs137852913; hg19: chr2-47132656;