10-17114152-A-G

Variant names:

• chr10-17114152-A-G
• rs1801222
• NM_001081.4:c.758T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001081.4(CUBN):​c.758T>C​(p.Phe253Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.677 in 1,612,932 control chromosomes in the GnomAD database, including 374,929 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.73 (40613 hom., cov: 32)
  • Exomes 𝑓: 0.67 (334316 hom.)
• Consequence: CUBN NM_001081.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 3.29
• Publications: 104 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=2.2720735E-6).
• BP6: Variant 10-17114152-A-G is Benign according to our data. Variant chr10-17114152-A-G is described in ClinVar as Benign. ClinVar VariationId is 299538.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.828 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001081.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CUBN	NM_001081.4	MANE Select	c.758T>C	p.Phe253Ser	missense	Exon 8 of 67	NP_001072.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CUBN	ENST00000377833.10	TSL:1 MANE Select	c.758T>C	p.Phe253Ser	missense	Exon 8 of 67	ENSP00000367064.4

Frequencies

GnomAD3 genomes AF: 0.726 AC: 110379 AN: 151968 Hom.: 40573 Cov.: 32

Gnomad AFR AF: 0.804

Gnomad AMI AF: 0.548

Gnomad AMR AF: 0.766

Gnomad ASJ AF: 0.774

Gnomad EAS AF: 0.822

Gnomad SAS AF: 0.849

Gnomad FIN AF: 0.694

Gnomad MID AF: 0.873

Gnomad NFE AF: 0.658

Gnomad OTH AF: 0.757

GnomAD2 exomes AF: 0.730 AC: 182046 AN: 249530 AF XY: 0.731

Gnomad AFR exome AF: 0.808

Gnomad AMR exome AF: 0.800

Gnomad ASJ exome AF: 0.765

Gnomad EAS exome AF: 0.806

Gnomad FIN exome AF: 0.689

Gnomad NFE exome AF: 0.661

Gnomad OTH exome AF: 0.730

GnomAD4 exome AF: 0.672 AC: 981670 AN: 1460846 Hom.: 334316 Cov.: 51 AF XY: 0.678 AC XY: 492317 AN XY: 726658

African (AFR) AF: 0.811 AC: 27140 AN: 33474

American (AMR) AF: 0.796 AC: 35532 AN: 44614

Ashkenazi Jewish (ASJ) AF: 0.767 AC: 20046 AN: 26122

East Asian (EAS) AF: 0.826 AC: 32761 AN: 39680

South Asian (SAS) AF: 0.836 AC: 71963 AN: 86078

European-Finnish (FIN) AF: 0.687 AC: 36649 AN: 53358

Middle Eastern (MID) AF: 0.882 AC: 5089 AN: 5768

European-Non Finnish (NFE) AF: 0.639 AC: 709701 AN: 1111392

Other (OTH) AF: 0.709 AC: 42789 AN: 60360

GnomAD4 genome AF: 0.726 AC: 110468 AN: 152086 Hom.: 40613 Cov.: 32 AF XY: 0.733 AC XY: 54478 AN XY: 74346

African (AFR) AF: 0.803 AC: 33329 AN: 41486

American (AMR) AF: 0.767 AC: 11726 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.774 AC: 2684 AN: 3468

East Asian (EAS) AF: 0.822 AC: 4245 AN: 5162

South Asian (SAS) AF: 0.850 AC: 4100 AN: 4826

European-Finnish (FIN) AF: 0.694 AC: 7326 AN: 10562

Middle Eastern (MID) AF: 0.884 AC: 260 AN: 294

European-Non Finnish (NFE) AF: 0.658 AC: 44695 AN: 67976

Other (OTH) AF: 0.760 AC: 1603 AN: 2110

Alfa AF: 0.688 Hom.: 134144

Bravo AF: 0.734

TwinsUK AF: 0.633 AC: 2349

ALSPAC AF: 0.635 AC: 2449

ESP6500AA AF: 0.800 AC: 3523

ESP6500EA AF: 0.647 AC: 5561

ExAC AF: 0.726 AC: 88089

Asia WGS AF: 0.832 AC: 2895 AN: 3478

EpiCase AF: 0.693

EpiControl AF: 0.696

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Jul 07, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 23824729, 19744961, 23754956)

Nov 21, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Imerslund-Grasbeck syndrome type 1 Benign:2

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.

Jul 30, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Imerslund-Grasbeck syndrome Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.063
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	9.2
DANN	Benign	0.67
DEOGEN2	Benign	0.035	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.022	N
LIST_S2	Benign	0.059	T
MetaRNN	Benign	0.0000023	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	-2.1	N
PhyloP100		3.3
PrimateAI	Benign	0.27	T
PROVEAN	Benign	3.8	N
REVEL	Benign	0.21
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.036
MPC		0.14
ClinPred		0.0019	T
GERP RS		2.5
Varity_R		0.046
gMVP		0.72
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: rs1801222; hg19: chr10-17156151; COSMIC: COSV107502665;