rs11254363

Variant names:

• chr10-17088694-A-G
• rs11254363
• NM_001081.4:c.1766-349T>C

Variant summary

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

The NM_001081.4(CUBN):​c.1766-349T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.263 in 152,142 control chromosomes in the GnomAD database, including 5,682 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 0.26 (5682 hom., cov: 32)
• Consequence: CUBN NM_001081.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.235
• Publications: 27 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 (AFR) allele frequency at 95% confidence interval = 0.299 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CUBN	NM_001081.4	c.1766-349T>C		intron_variant	Intron 14 of 66	ENST00000377833.10	NP_001072.2
CUBN	XM_011519708.3	c.1766-349T>C		intron_variant	Intron 14 of 54		XP_011518010.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CUBN	ENST00000377833.10	c.1766-349T>C		intron_variant	Intron 14 of 66	1	NM_001081.4	ENSP00000367064.4

Frequencies

GnomAD3 genomes AF: 0.263 AC: 39940 AN: 152024 Hom.: 5680 Cov.: 32

Gnomad AFR AF: 0.303

Gnomad AMI AF: 0.305

Gnomad AMR AF: 0.234

Gnomad ASJ AF: 0.420

Gnomad EAS AF: 0.0256

Gnomad SAS AF: 0.285

Gnomad FIN AF: 0.245

Gnomad MID AF: 0.478

Gnomad NFE AF: 0.253

Gnomad OTH AF: 0.315

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

GnomAD4 genome AF: 0.263 AC: 39963 AN: 152142 Hom.: 5682 Cov.: 32 AF XY: 0.262 AC XY: 19475 AN XY: 74384

African (AFR) AF: 0.303 AC: 12579 AN: 41498

American (AMR) AF: 0.234 AC: 3576 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.420 AC: 1455 AN: 3468

East Asian (EAS) AF: 0.0257 AC: 133 AN: 5182

South Asian (SAS) AF: 0.285 AC: 1371 AN: 4810

European-Finnish (FIN) AF: 0.245 AC: 2596 AN: 10590

Middle Eastern (MID) AF: 0.480 AC: 141 AN: 294

European-Non Finnish (NFE) AF: 0.253 AC: 17176 AN: 67988

Other (OTH) AF: 0.311 AC: 658 AN: 2114

Alfa AF: 0.254 Hom.: 17165

Bravo AF: 0.262

Asia WGS AF: 0.133 AC: 466 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	4.4
DANN	Benign	0.49
PhyloP100		0.23
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: rs11254363; hg19: chr10-17130693;