10-16876998-T-C

Variant names:

• chr10-16876998-T-C
• rs1801240
• NM_001081.4:c.9005A>G

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.9005A>G​(p.Glu3002Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.107 in 1,613,950 control chromosomes in the GnomAD database, including 10,219 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.13 (1445 hom., cov: 32)
  • Exomes 𝑓: 0.11 (8774 hom.)
• Consequence: CUBN NM_001081.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 2.83
• Publications: 16 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=0.0023685992).
• BP6: Variant 10-16876998-T-C is Benign according to our data. Variant chr10-16876998-T-C is described in ClinVar as Benign. ClinVar VariationId is 299388.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.201 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CUBN	NM_001081.4	c.9005A>G	p.Glu3002Gly	missense_variant	Exon 57 of 67	ENST00000377833.10	NP_001072.2
CUBN	XM_011519709.3	c.4991A>G	p.Glu1664Gly	missense_variant	Exon 31 of 41		XP_011518011.1
CUBN	XM_011519710.3	c.4967A>G	p.Glu1656Gly	missense_variant	Exon 31 of 41		XP_011518012.1
CUBN	XM_011519711.4	c.4847A>G	p.Glu1616Gly	missense_variant	Exon 30 of 40		XP_011518013.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CUBN	ENST00000377833.10	c.9005A>G	p.Glu3002Gly	missense_variant	Exon 57 of 67	1	NM_001081.4	ENSP00000367064.4

Frequencies

GnomAD3 genomes AF: 0.129 AC: 19609 AN: 152024 Hom.: 1442 Cov.: 32

Gnomad AFR AF: 0.204

Gnomad AMI AF: 0.123

Gnomad AMR AF: 0.0992

Gnomad ASJ AF: 0.151

Gnomad EAS AF: 0.00212

Gnomad SAS AF: 0.134

Gnomad FIN AF: 0.0788

Gnomad MID AF: 0.136

Gnomad NFE AF: 0.106

Gnomad OTH AF: 0.127

GnomAD2 exomes AF: 0.104 AC: 26075 AN: 251364 AF XY: 0.105

Gnomad AFR exome AF: 0.210

Gnomad AMR exome AF: 0.0799

Gnomad ASJ exome AF: 0.141

Gnomad EAS exome AF: 0.00185

Gnomad FIN exome AF: 0.0757

Gnomad NFE exome AF: 0.104

Gnomad OTH exome AF: 0.105

GnomAD4 exome AF: 0.105 AC: 153749 AN: 1461808 Hom.: 8774 Cov.: 33 AF XY: 0.106 AC XY: 77090 AN XY: 727208

African (AFR) AF: 0.212 AC: 7105 AN: 33478

American (AMR) AF: 0.0826 AC: 3693 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.138 AC: 3595 AN: 26136

East Asian (EAS) AF: 0.00126 AC: 50 AN: 39698

South Asian (SAS) AF: 0.141 AC: 12158 AN: 86254

European-Finnish (FIN) AF: 0.0792 AC: 4232 AN: 53420

Middle Eastern (MID) AF: 0.140 AC: 808 AN: 5768

European-Non Finnish (NFE) AF: 0.104 AC: 115516 AN: 1111936

Other (OTH) AF: 0.109 AC: 6592 AN: 60394

GnomAD4 genome AF: 0.129 AC: 19615 AN: 152142 Hom.: 1445 Cov.: 32 AF XY: 0.125 AC XY: 9299 AN XY: 74386

African (AFR) AF: 0.204 AC: 8476 AN: 41504

American (AMR) AF: 0.0990 AC: 1511 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.151 AC: 523 AN: 3472

East Asian (EAS) AF: 0.00213 AC: 11 AN: 5168

South Asian (SAS) AF: 0.134 AC: 644 AN: 4820

European-Finnish (FIN) AF: 0.0788 AC: 835 AN: 10602

Middle Eastern (MID) AF: 0.136 AC: 40 AN: 294

European-Non Finnish (NFE) AF: 0.106 AC: 7199 AN: 67994

Other (OTH) AF: 0.125 AC: 264 AN: 2110

Alfa AF: 0.113 Hom.: 2381

Bravo AF: 0.134

TwinsUK AF: 0.110 AC: 407

ALSPAC AF: 0.100 AC: 387

ESP6500AA AF: 0.204 AC: 899

ESP6500EA AF: 0.105 AC: 902

ExAC AF: 0.107 AC: 13049

Asia WGS AF: 0.0760 AC: 265 AN: 3478

EpiCase AF: 0.109

EpiControl AF: 0.108

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Sep 07, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Imerslund-Grasbeck syndrome type 1 Benign:1

Jan 12, 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. -

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 v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.73	T
BayesDel_noAF	Benign	-0.68
CADD	Benign	21
DANN	Benign	0.96
DEOGEN2	Benign	0.15	T
Eigen	Benign	-0.46
Eigen_PC	Benign	-0.41
FATHMM_MKL	Benign	0.20	N
LIST_S2	Benign	0.48	T
MetaRNN	Benign	0.0024	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.6	L
PhyloP100		2.8
PrimateAI	Benign	0.37	T
PROVEAN	Uncertain	-2.8	D
REVEL	Benign	0.084
Sift	Benign	0.24	T
Sift4G	Benign	0.12	T
Polyphen		0.0060	B
Vest4		0.058
MPC		0.12
ClinPred		0.012	T
GERP RS		5.8
Varity_R		0.22
gMVP		0.55
Mutation Taster		=86/14	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: rs1801240; hg19: chr10-16918997; COSMIC: COSV64710700;