10-17115487-C-T

Position:

• chr10-17115487-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001081.4(CUBN):​c.704G>A​(p.Arg235Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,786 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: CUBN NM_001081.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.14

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CUBN	NM_001081.4	c.704G>A	p.Arg235Gln	missense_variant	7/67	ENST00000377833.10	NP_001072.2
CUBN	XM_011519708.3	c.704G>A	p.Arg235Gln	missense_variant	7/55		XP_011518010.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CUBN	ENST00000377833.10	c.704G>A	p.Arg235Gln	missense_variant	7/67	1	NM_001081.4	ENSP00000367064.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251360 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135848

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461786 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727182

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Imerslund-Grasbeck syndrome type 1;C5394384:Proteinuria, chronic benign Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Apr 03, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.38
BayesDel_addAF	Benign	-0.050	T
BayesDel_noAF	Benign	-0.14
CADD	Pathogenic	26
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.22	T
Eigen	Uncertain	0.50
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.84	T
M_CAP	Benign	0.057	D
MetaRNN	Uncertain	0.71	D
MetaSVM	Uncertain	0.58	D
MutationAssessor	Uncertain	2.6	M
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-1.9	N
REVEL	Uncertain	0.43
Sift	Uncertain	0.018	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.53
MutPred		0.45		Gain of disorder (P = 0.1734);
MVP		0.95
MPC		0.48
ClinPred		0.93	D
GERP RS		4.6
Varity_R		0.23
gMVP		0.80

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs752992672; hg19: chr10-17157486; COSMIC: COSV64725404;