rs1801240

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chr10-16876998-T-C
• chr10-16876998-T-A

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: Laboratory for Molecular Medicine, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• 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.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CUBN	NM_001081.4	MANE Select	c.9005A>G	p.Glu3002Gly	missense	Exon 57 of 67	NP_001072.2	O60494

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CUBN	ENST00000377833.10	TSL:1 MANE Select	c.9005A>G	p.Glu3002Gly	missense	Exon 57 of 67	ENSP00000367064.4	O60494

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

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Imerslund-Grasbeck syndrome (1)
-	-	1	Imerslund-Grasbeck syndrome type 1 (1)

Computational scores

Source: dbNSFP v4.9

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;