chr10-17085639-T-C

Position:

• chr10-17085639-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP5

The NM_001081.4(CUBN):​c.2068A>G​(p.Ile690Val) 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 benign outcome for this variant. 14/25 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CUBN NM_001081.4 missense
• Clinical Significance: Likely pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 0.576

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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 10-17085639-T-C is Pathogenic according to our data. Variant chr10-17085639-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 56325.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CUBN	NM_001081.4	c.2068A>G	p.Ile690Val	missense_variant	16/67	ENST00000377833.10	NP_001072.2
CUBN	XM_011519708.3	c.2068A>G	p.Ile690Val	missense_variant	16/55		XP_011518010.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CUBN	ENST00000377833.10	c.2068A>G	p.Ile690Val	missense_variant	16/67	1	NM_001081.4	ENSP00000367064.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Imerslund-Grasbeck syndrome Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM)

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	19
DANN	Benign	0.18
DEOGEN2	Benign	0.023	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-0.96
FATHMM_MKL	Benign	0.049	N
LIST_S2	Benign	0.79	T
M_CAP	Benign	0.0060	T
MetaRNN	Benign	0.035	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	-0.34	N
PrimateAI	Benign	0.32	T
PROVEAN	Benign	0.28	N
REVEL	Benign	0.23
Sift	Benign	1.0	T
Sift4G	Benign	0.90	T
Polyphen		0.0010	B
Vest4		0.098
MutPred		0.49		Loss of sheet (P = 0.1398);
MVP		0.18
MPC		0.068
ClinPred		0.043	T
GERP RS		1.4
Varity_R		0.022
gMVP		0.15

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.99		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.99		Position offset: 1
DS_DL_spliceai		0.87		Position offset: -42

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

Publications

LitVar

Other links and lift over

dbSNP: rs386833772; hg19: chr10-17127638;