rs1801230

Variant names:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001081.4(CUBN):c.10265C>T(p.Thr3422Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0233 in 1,614,004 control chromosomes in the GnomAD database, including 508 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.017 ( 29 hom., cov: 33)

Exomes 𝑓: 0.024 ( 479 hom. )

Consequence

CUBN
NM_001081.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 1.89

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.009336919).

BP6

Variant 10-16835111-G-A is Benign according to our data. Variant chr10-16835111-G-A is described in ClinVar as [Benign]. Clinvar id is 299364.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-16835111-G-A is described in Lovd as [Benign]. Variant chr10-16835111-G-A is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0167 (2539/152218) while in subpopulation NFE AF= 0.0271 (1842/68002). AF 95% confidence interval is 0.0261. There are 29 homozygotes in gnomad4. There are 1168 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 29 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CUBN	NM_001081.4 link	c.10265C>T	p.Thr3422Ile	missense_variant	Exon 64 of 67	ENST00000377833.10	NP_001072.2	O60494
CUBN	XM_011519709.3 link	c.6251C>T	p.Thr2084Ile	missense_variant	Exon 38 of 41		XP_011518011.1
CUBN	XM_011519710.3 link	c.6227C>T	p.Thr2076Ile	missense_variant	Exon 38 of 41		XP_011518012.1
CUBN	XM_011519711.4 link	c.6107C>T	p.Thr2036Ile	missense_variant	Exon 37 of 40		XP_011518013.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CUBN	ENST00000377833.10 link	c.10265C>T	p.Thr3422Ile	missense_variant	Exon 64 of 67	1	NM_001081.4	ENSP00000367064.4		O60494

Frequencies

GnomAD3 genomes

AF:

0.0167

AC:

2539

AN:

152100

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00466

Gnomad AMI

AF:

0.0439

Gnomad AMR

AF:

0.0109

Gnomad ASJ

AF:

0.0332

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00435

Gnomad FIN

AF:

0.0112

Gnomad MID

AF:

0.0382

Gnomad NFE

AF:

0.0271

Gnomad OTH

AF:

0.0139

GnomAD3 exomes

AF:

0.0175

AC:

4406

AN:

251256

Hom.:

AF XY:

0.0179

AC XY:

2425

AN XY:

135776

show subpopulations

Gnomad AFR exome

AF:

0.00535

Gnomad AMR exome

AF:

0.00824

Gnomad ASJ exome

AF:

0.0334

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00451

Gnomad FIN exome

AF:

0.0136

Gnomad NFE exome

AF:

0.0279

Gnomad OTH exome

AF:

0.0165

GnomAD4 exome

AF:

0.0240

AC:

35145

AN:

1461786

Hom.:

479

Cov.:

AF XY:

0.0235

AC XY:

17103

AN XY:

727206

show subpopulations

Gnomad4 AFR exome

AF:

0.00487

Gnomad4 AMR exome

AF:

0.00894

Gnomad4 ASJ exome

AF:

0.0357

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.00485

Gnomad4 FIN exome

AF:

0.0125

Gnomad4 NFE exome

AF:

0.0279

Gnomad4 OTH exome

AF:

0.0235

GnomAD4 genome

AF:

0.0167

AC:

2539

AN:

152218

Hom.:

Cov.:

AF XY:

0.0157

AC XY:

1168

AN XY:

74418

show subpopulations

Gnomad4 AFR

AF:

0.00467

Gnomad4 AMR

AF:

0.0109

Gnomad4 ASJ

AF:

0.0332

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00415

Gnomad4 FIN

AF:

0.0112

Gnomad4 NFE

AF:

0.0271

Gnomad4 OTH

AF:

0.0142

Alfa

AF:

0.0252

Hom.:

Bravo

AF:

0.0177

TwinsUK

AF:

0.0297

AC:

110

ALSPAC

AF:

0.0327

AC:

126

ESP6500AA

AF:

0.00658

AC:

ESP6500EA

AF:

0.0288

AC:

248

ExAC

AF:

0.0183

AC:

2224

Asia WGS

AF:

0.00404

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Oct 29, 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

- -

Feb 26, 2020

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 26827111) -

Nov 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

CUBN: BP4, BS1, BS2 -

Imerslund-Grasbeck syndrome type 1

Benign:1

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. -

Imerslund-Grasbeck syndrome

Benign:1

Feb 02, 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

0.093

BayesDel_addAF

Benign

-0.65

BayesDel_noAF

Benign

-0.69

CADD

Benign

9.4

DANN

Uncertain

0.98

DEOGEN2

Benign

0.15

Eigen

Benign

-0.27

Eigen_PC

Benign

-0.27

FATHMM_MKL

Uncertain

0.91

LIST_S2

Benign

0.42

MetaRNN

Benign

0.0093

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.1

PrimateAI

Benign

0.36

PROVEAN

Uncertain

-2.9

REVEL

Benign

0.098

Sift

Benign

0.34

Sift4G

Benign

0.11

Polyphen

0.70

Vest4

0.074

MPC

0.13

ClinPred

0.035

GERP RS

3.9

Varity_R

0.084

gMVP

0.49

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over