rs2281649

Variant names:

• chr10-17114528-C-T
• rs2281649
• NM_001081.4:c.721-339G>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.721-339G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.239 in 152,092 control chromosomes in the GnomAD database, including 4,709 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 0.24 (4709 hom., cov: 32)
• Consequence: CUBN NM_001081.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.24
• Publications: 10 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=-0.64).
• BA1: GnomAd4 highest subpopulation (AFR) 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.721-339G>A		intron_variant	Intron 7 of 66	ENST00000377833.10	NP_001072.2
CUBN	XM_011519708.3	c.721-339G>A		intron_variant	Intron 7 of 54		XP_011518010.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CUBN	ENST00000377833.10	c.721-339G>A		intron_variant	Intron 7 of 66	1	NM_001081.4	ENSP00000367064.4

Frequencies

GnomAD3 genomes AF: 0.239 AC: 36323 AN: 151976 Hom.: 4706 Cov.: 32

Gnomad AFR AF: 0.310

Gnomad AMI AF: 0.163

Gnomad AMR AF: 0.225

Gnomad ASJ AF: 0.297

Gnomad EAS AF: 0.223

Gnomad SAS AF: 0.170

Gnomad FIN AF: 0.278

Gnomad MID AF: 0.315

Gnomad NFE AF: 0.196

Gnomad OTH AF: 0.262

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

GnomAD4 genome AF: 0.239 AC: 36343 AN: 152092 Hom.: 4709 Cov.: 32 AF XY: 0.240 AC XY: 17815 AN XY: 74336

African (AFR) AF: 0.309 AC: 12817 AN: 41448

American (AMR) AF: 0.225 AC: 3441 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.297 AC: 1030 AN: 3470

East Asian (EAS) AF: 0.223 AC: 1156 AN: 5180

South Asian (SAS) AF: 0.172 AC: 830 AN: 4826

European-Finnish (FIN) AF: 0.278 AC: 2939 AN: 10576

Middle Eastern (MID) AF: 0.322 AC: 94 AN: 292

European-Non Finnish (NFE) AF: 0.196 AC: 13338 AN: 67982

Other (OTH) AF: 0.260 AC: 549 AN: 2112

Alfa AF: 0.209 Hom.: 2868

Bravo AF: 0.240

Asia WGS AF: 0.198 AC: 692 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.64
CADD	Benign	9.6
DANN	Benign	0.69
PhyloP100		-1.2
Mutation Taster		=99/1	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: rs2281649; hg19: chr10-17156527;