chr2-46902363-G-C

Position:

• chr2-46902363-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_139279.6(MCFD2):​c.*3100C>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0327 in 152,638 control chromosomes in the GnomAD database, including 103 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.033 (103 hom., cov: 33)
  • Exomes 𝑓: 0.016 (0 hom.)
• Consequence: MCFD2 NM_139279.6 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.880

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 2-46902363-G-C is Benign according to our data. Variant chr2-46902363-G-C is described in ClinVar as [Benign]. Clinvar id is 336328.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0327 (4981/152206) while in subpopulation NFE AF= 0.0472 (3213/68022). AF 95% confidence interval is 0.0459. There are 103 homozygotes in gnomad4. There are 2348 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 103 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MCFD2	NM_139279.6	c.*3100C>G		3_prime_UTR_variant	4/4	ENST00000319466.9	NP_644808.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MCFD2	ENST00000319466.9	c.*3100C>G		3_prime_UTR_variant	4/4	1	NM_139279.6	ENSP00000317271	P1
	ENST00000429761.1	n.40+3049G>C		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.0328 AC: 4983 AN: 152088 Hom.: 103 Cov.: 33

Gnomad AFR AF: 0.0137

Gnomad AMI AF: 0.0779

Gnomad AMR AF: 0.0267

Gnomad ASJ AF: 0.0660

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.00871

Gnomad FIN AF: 0.0325

Gnomad MID AF: 0.0348

Gnomad NFE AF: 0.0472

Gnomad OTH AF: 0.0474

GnomAD4 exome AF: 0.0162 AC: 7 AN: 432 Hom.: 0 Cov.: 0 AF XY: 0.0192 AC XY: 5 AN XY: 260

Gnomad4 FIN exome AF: 0.0164

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0327 AC: 4981 AN: 152206 Hom.: 103 Cov.: 33 AF XY: 0.0316 AC XY: 2348 AN XY: 74406

Gnomad4 AFR AF: 0.0136

Gnomad4 AMR AF: 0.0267

Gnomad4 ASJ AF: 0.0660

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.00830

Gnomad4 FIN AF: 0.0325

Gnomad4 NFE AF: 0.0472

Gnomad4 OTH AF: 0.0469

Alfa AF: 0.0413 Hom.: 22

Bravo AF: 0.0317

Asia WGS AF: 0.00924 AC: 32 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Factor 5 and Factor VIII, combined deficiency of, 2 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	8.6
DANN	Benign	0.75

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

Publications

LitVar

Other links and lift over

dbSNP: rs13424086; hg19: chr2-47129502;