10-17002696-C-T

Variant names:

• chr10-17002696-C-T
• rs7094474
• NM_001081.4:c.4169-12181G>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.4169-12181G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.4 in 151,938 control chromosomes in the GnomAD database, including 12,457 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 0.40 (12457 hom., cov: 32)
• Consequence: CUBN NM_001081.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.243
• Publications: 3 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=-0.83).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.569 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CUBN	NM_001081.4	c.4169-12181G>A		intron_variant	Intron 28 of 66	ENST00000377833.10	NP_001072.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CUBN	ENST00000377833.10	c.4169-12181G>A		intron_variant	Intron 28 of 66	1	NM_001081.4	ENSP00000367064.4

Frequencies

GnomAD3 genomes AF: 0.400 AC: 60745 AN: 151820 Hom.: 12447 Cov.: 32

Gnomad AFR AF: 0.310

Gnomad AMI AF: 0.300

Gnomad AMR AF: 0.457

Gnomad ASJ AF: 0.416

Gnomad EAS AF: 0.586

Gnomad SAS AF: 0.378

Gnomad FIN AF: 0.427

Gnomad MID AF: 0.351

Gnomad NFE AF: 0.426

Gnomad OTH AF: 0.388

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

GnomAD4 genome AF: 0.400 AC: 60802 AN: 151938 Hom.: 12457 Cov.: 32 AF XY: 0.400 AC XY: 29711 AN XY: 74280

African (AFR) AF: 0.311 AC: 12882 AN: 41434

American (AMR) AF: 0.457 AC: 6981 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.416 AC: 1442 AN: 3470

East Asian (EAS) AF: 0.587 AC: 3018 AN: 5142

South Asian (SAS) AF: 0.378 AC: 1822 AN: 4818

European-Finnish (FIN) AF: 0.427 AC: 4504 AN: 10558

Middle Eastern (MID) AF: 0.357 AC: 105 AN: 294

European-Non Finnish (NFE) AF: 0.426 AC: 28970 AN: 67932

Other (OTH) AF: 0.382 AC: 804 AN: 2102

Alfa AF: 0.417 Hom.: 1760

Bravo AF: 0.408

Asia WGS AF: 0.437 AC: 1520 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	3.1
DANN	Benign	0.42
PhyloP100		-0.24
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: rs7094474; hg19: chr10-17044695;