2-46902702-A-G

Variant names:

• chr2-46902702-A-G
• rs193204253
• NM_139279.6:c.*2761T>C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_139279.6(MCFD2):​c.*2761T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0129 in 152,650 control chromosomes in the GnomAD database, including 24 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.013 (24 hom., cov: 33)
  • Exomes 𝑓: 0.047 (0 hom.)
• Consequence: MCFD2 NM_139279.6 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.234

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):

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.69).
• BP6: Variant 2-46902702-A-G is Benign according to our data. Variant chr2-46902702-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 896348.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0128 (1947/152330) while in subpopulation NFE AF= 0.0173 (1179/68030). AF 95% confidence interval is 0.0165. There are 24 homozygotes in gnomad4. There are 980 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 24 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MCFD2	NM_139279.6	c.*2761T>C		3_prime_UTR_variant	Exon 4 of 4	ENST00000319466.9	NP_644808.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MCFD2	ENST00000319466	c.*2761T>C		3_prime_UTR_variant	Exon 4 of 4	1	NM_139279.6	ENSP00000317271.4

Frequencies

GnomAD3 genomes AF: 0.0128 AC: 1947 AN: 152212 Hom.: 24 Cov.: 33

Gnomad AFR AF: 0.00357

Gnomad AMI AF: 0.0263

Gnomad AMR AF: 0.00694

Gnomad ASJ AF: 0.00230

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00476

Gnomad FIN AF: 0.0411

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0173

Gnomad OTH AF: 0.0105

GnomAD4 exome AF: 0.0469 AC: 15 AN: 320 Hom.: 0 Cov.: 0 AF XY: 0.0657 AC XY: 13 AN XY: 198

Gnomad4 FIN exome AF: 0.0452

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.250

GnomAD4 genome AF: 0.0128 AC: 1947 AN: 152330 Hom.: 24 Cov.: 33 AF XY: 0.0132 AC XY: 980 AN XY: 74492

Gnomad4 AFR AF: 0.00356

Gnomad4 AMR AF: 0.00693

Gnomad4 ASJ AF: 0.00230

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00476

Gnomad4 FIN AF: 0.0411

Gnomad4 NFE AF: 0.0173

Gnomad4 OTH AF: 0.0104

Alfa AF: 0.0161 Hom.: 4

Bravo AF: 0.0102

Asia WGS AF: 0.00231 AC: 8 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.69
CADD	Benign	12
DANN	Benign	0.88
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs193204253; hg19: chr2-47129841;