rs1801239

chr10-16877053-T-Achr10-16877053-T-Cchr10-16877053-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001081.4(CUBN):c.8950A>T(p.Ile2984Phe) 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I2984V) has been classified as Benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CUBN NM_001081.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.65

Genes affected

CUBN (HGNC:2548): (cubilin) Cubilin (CUBN) acts as a receptor for intrinsic factor-vitamin B12 complexes. The role of receptor is supported by the presence of 27 CUB domains. Cubulin is located within the epithelium of intestine and kidney. Mutations in CUBN may play a role in autosomal recessive megaloblastic anemia. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.881

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CUBN	NM_001081.4	c.8950A>T	p.Ile2984Phe	missense_variant	57/67	ENST00000377833.10
CUBN	XM_011519709.3	c.4936A>T	p.Ile1646Phe	missense_variant	31/41
CUBN	XM_011519710.3	c.4912A>T	p.Ile1638Phe	missense_variant	31/41
CUBN	XM_011519711.4	c.4792A>T	p.Ile1598Phe	missense_variant	30/40

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CUBN	ENST00000377833.10	c.8950A>T	p.Ile2984Phe	missense_variant	57/67	1	NM_001081.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Benign	-0.0066	T
BayesDel_noAF	Benign	-0.25
Cadd	Benign	20
Dann	Uncertain	0.98
DEOGEN2	Benign	0.23	T
Eigen	Uncertain	0.36
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Benign	0.71	T
M_CAP	Benign	0.029	D
MetaRNN	Pathogenic	0.88	D
MetaSVM	Benign	-0.33	T
MutationAssessor	Uncertain	2.6	M
MutationTaster	Benign	1.0	D
PrimateAI	Benign	0.43	T
PROVEAN	Uncertain	-2.8	D
REVEL	Uncertain	0.40
Sift	Uncertain	0.0040	D
Sift4G	Pathogenic	0.0010	D
Polyphen		0.88	P
Vest4		0.72
MutPred		0.69		Loss of sheet (P = 0.0457);
MVP		0.85
MPC		0.51
ClinPred		0.97	D
GERP RS		3.6
Varity_R		0.49
gMVP		0.85

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr10-16919052;