chr2-46917064-C-G

Variant names:

• chr2-46917064-C-G
• rs13388612
• NM_001288953.2:c.-12-120C>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001288953.2(TTC7A):​c.-12-120C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0887 in 643,898 control chromosomes in the GnomAD database, including 3,680 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.13 (1734 hom., cov: 32)
  • Exomes 𝑓: 0.077 (1946 hom.)
• Consequence: TTC7A NM_001288953.2 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.26
• Publications: 2 publications found

Genes affected

TTC7A (HGNC:19750): (tetratricopeptide repeat domain 7A) This gene encodes a protein containing tetratricopeptide repeats. Mutations in this gene disrupt intestinal development and can cause early onset inflammatory bowel disease and intestinal atresia. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jun 2014]

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]

MCFD2 Gene-Disease associations (from GenCC):

• factor 5 and Factor VIII, combined deficiency of, 2

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), Ambry Genetics, Genomics England PanelApp
• combined deficiency of factor V and factor VIII

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.98).
• BP6: Variant 2-46917064-C-G is Benign according to our data. Variant chr2-46917064-C-G is described in ClinVar as Benign. ClinVar VariationId is 1249964.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.25 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001288953.2. 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
	TTC7A	NM_001288953.2		c.-12-120C>G		intron	N/A	NP_001275882.1	G5E9G4
	MCFD2	NM_001171508.2		c.-6-7887G>C		intron	N/A	NP_001164979.1	Q8NI22-1
	MCFD2	NM_001171511.3		c.93-9095G>C		intron	N/A	NP_001164982.1	Q8NI22-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTC7A	ENST00000409245.5	TSL:2	c.-12-120C>G		intron	N/A	ENSP00000386307.1	G5E9G4
	MCFD2	ENST00000409207.5	TSL:2	c.-6-7887G>C		intron	N/A	ENSP00000386386.1	Q8NI22-1
	MCFD2	ENST00000895741.1		c.-100-6191G>C		intron	N/A	ENSP00000565800.1

Frequencies

GnomAD3 genomes AF: 0.125 AC: 19002 AN: 152072 Hom.: 1724 Cov.: 32

Gnomad AFR AF: 0.254

Gnomad AMI AF: 0.0921

Gnomad AMR AF: 0.121

Gnomad ASJ AF: 0.0685

Gnomad EAS AF: 0.0946

Gnomad SAS AF: 0.0597

Gnomad FIN AF: 0.0743

Gnomad MID AF: 0.0443

Gnomad NFE AF: 0.0662

Gnomad OTH AF: 0.121

GnomAD4 exome AF: 0.0775 AC: 38097 AN: 491708 Hom.: 1946 AF XY: 0.0748 AC XY: 19885 AN XY: 265990

African (AFR) AF: 0.256 AC: 3344 AN: 13064

American (AMR) AF: 0.132 AC: 3172 AN: 24030

Ashkenazi Jewish (ASJ) AF: 0.0679 AC: 1109 AN: 16342

East Asian (EAS) AF: 0.123 AC: 3847 AN: 31202

South Asian (SAS) AF: 0.0569 AC: 2971 AN: 52196

European-Finnish (FIN) AF: 0.0615 AC: 1903 AN: 30952

Middle Eastern (MID) AF: 0.0628 AC: 136 AN: 2164

European-Non Finnish (NFE) AF: 0.0658 AC: 19336 AN: 293848

Other (OTH) AF: 0.0817 AC: 2279 AN: 27910

GnomAD4 genome AF: 0.125 AC: 19048 AN: 152190 Hom.: 1734 Cov.: 32 AF XY: 0.125 AC XY: 9306 AN XY: 74406

African (AFR) AF: 0.254 AC: 10539 AN: 41492

American (AMR) AF: 0.121 AC: 1853 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.0685 AC: 238 AN: 3472

East Asian (EAS) AF: 0.0950 AC: 493 AN: 5188

South Asian (SAS) AF: 0.0595 AC: 287 AN: 4822

European-Finnish (FIN) AF: 0.0743 AC: 787 AN: 10596

Middle Eastern (MID) AF: 0.0442 AC: 13 AN: 294

European-Non Finnish (NFE) AF: 0.0662 AC: 4501 AN: 68012

Other (OTH) AF: 0.120 AC: 253 AN: 2116

Alfa AF: 0.0306 Hom.: 24

Bravo AF: 0.136

Asia WGS AF: 0.103 AC: 358 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.98
CADD	Benign	0.76
DANN	Benign	0.40
PhyloP100		-1.3
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs13388612; hg19: chr2-47144203; COSMIC: COSV60177819; COSMIC: COSV60177819;