rs10904831

Variant names:

• chr10-16889345-C-T
• rs10904831
• NM_001081.4:c.8756-779G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001081.4(CUBN):​c.8756-779G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.08 in 152,202 control chromosomes in the GnomAD database, including 969 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.080 (969 hom., cov: 32)
• Consequence: CUBN NM_001081.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.441
• Publications: 5 publications found

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]

CUBN Gene-Disease associations (from GenCC):

• Imerslund-Grasbeck syndrome type 1

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Laboratory for Molecular Medicine
• proteinuria, chronic benign

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• Imerslund-Grasbeck syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.305 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CUBN	NM_001081.4	c.8756-779G>A		intron_variant	Intron 55 of 66	ENST00000377833.10	NP_001072.2
CUBN	XM_011519709.3	c.4742-779G>A		intron_variant	Intron 29 of 40		XP_011518011.1
CUBN	XM_011519710.3	c.4718-779G>A		intron_variant	Intron 29 of 40		XP_011518012.1
CUBN	XM_011519711.4	c.4598-779G>A		intron_variant	Intron 28 of 39		XP_011518013.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CUBN	ENST00000377833.10	c.8756-779G>A		intron_variant	Intron 55 of 66	1	NM_001081.4	ENSP00000367064.4

Frequencies

GnomAD3 genomes AF: 0.0798 AC: 12141 AN: 152084 Hom.: 955 Cov.: 32

Gnomad AFR AF: 0.0174

Gnomad AMI AF: 0.144

Gnomad AMR AF: 0.205

Gnomad ASJ AF: 0.0568

Gnomad EAS AF: 0.317

Gnomad SAS AF: 0.156

Gnomad FIN AF: 0.130

Gnomad MID AF: 0.0411

Gnomad NFE AF: 0.0588

Gnomad OTH AF: 0.0866

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.0800 AC: 12183 AN: 152202 Hom.: 969 Cov.: 32 AF XY: 0.0886 AC XY: 6591 AN XY: 74406

African (AFR) AF: 0.0176 AC: 731 AN: 41556

American (AMR) AF: 0.206 AC: 3152 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.0568 AC: 197 AN: 3470

East Asian (EAS) AF: 0.318 AC: 1640 AN: 5164

South Asian (SAS) AF: 0.155 AC: 748 AN: 4824

European-Finnish (FIN) AF: 0.130 AC: 1375 AN: 10576

Middle Eastern (MID) AF: 0.0374 AC: 11 AN: 294

European-Non Finnish (NFE) AF: 0.0588 AC: 3998 AN: 68000

Other (OTH) AF: 0.0947 AC: 200 AN: 2112

Alfa AF: 0.0757 Hom.: 413

Bravo AF: 0.0876

Asia WGS AF: 0.244 AC: 847 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.81
DANN	Benign	0.23
PhyloP100		-0.44
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs10904831; hg19: chr10-16931344;