10-16925587-C-G

Variant names:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001081.4(CUBN):c.6459G>C(p.Leu2153Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.124 in 1,613,578 control chromosomes in the GnomAD database, including 12,869 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.13 ( 1241 hom., cov: 32)

Exomes 𝑓: 0.12 ( 11628 hom. )

Consequence

CUBN
NM_001081.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 0.0550

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=0.002035886).

BP6

Variant 10-16925587-C-G is Benign according to our data. Variant chr10-16925587-C-G is described in ClinVar as [Benign]. Clinvar id is 299438.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.164 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CUBN	NM_001081.4 link	c.6459G>C	p.Leu2153Phe	missense_variant	Exon 42 of 67	ENST00000377833.10	NP_001072.2	O60494

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CUBN	ENST00000377833.10 link	c.6459G>C	p.Leu2153Phe	missense_variant	Exon 42 of 67	1	NM_001081.4	ENSP00000367064.4		O60494

Frequencies

GnomAD3 genomes

AF:

0.129

AC:

19587

AN:

152016

Hom.:

1242

Cov.:

show subpopulations

Gnomad AFR

AF:

0.138

Gnomad AMI

AF:

0.217

Gnomad AMR

AF:

0.123

Gnomad ASJ

AF:

0.164

Gnomad EAS

AF:

0.0621

Gnomad SAS

AF:

0.173

Gnomad FIN

AF:

0.136

Gnomad MID

AF:

0.155

Gnomad NFE

AF:

0.122

Gnomad OTH

AF:

0.133

GnomAD3 exomes

AF:

0.130

AC:

32624

AN:

251116

Hom.:

2355

AF XY:

0.131

AC XY:

17814

AN XY:

135770

show subpopulations

Gnomad AFR exome

AF:

0.135

Gnomad AMR exome

AF:

0.145

Gnomad ASJ exome

AF:

0.153

Gnomad EAS exome

AF:

0.0534

Gnomad SAS exome

AF:

0.178

Gnomad FIN exome

AF:

0.132

Gnomad NFE exome

AF:

0.121

Gnomad OTH exome

AF:

0.136

GnomAD4 exome

AF:

0.123

AC:

180333

AN:

1461444

Hom.:

11628

Cov.:

AF XY:

0.125

AC XY:

90722

AN XY:

727058

show subpopulations

Gnomad4 AFR exome

AF:

0.138

Gnomad4 AMR exome

AF:

0.143

Gnomad4 ASJ exome

AF:

0.151

Gnomad4 EAS exome

AF:

0.0702

Gnomad4 SAS exome

AF:

0.177

Gnomad4 FIN exome

AF:

0.133

Gnomad4 NFE exome

AF:

0.119

Gnomad4 OTH exome

AF:

0.126

GnomAD4 genome

AF:

0.129

AC:

19600

AN:

152134

Hom.:

1241

Cov.:

AF XY:

0.129

AC XY:

9600

AN XY:

74378

show subpopulations

Gnomad4 AFR

AF:

0.138

Gnomad4 AMR

AF:

0.123

Gnomad4 ASJ

AF:

0.164

Gnomad4 EAS

AF:

0.0625

Gnomad4 SAS

AF:

0.173

Gnomad4 FIN

AF:

0.136

Gnomad4 NFE

AF:

0.122

Gnomad4 OTH

AF:

0.130

Alfa

AF:

0.103

Hom.:

330

Bravo

AF:

0.127

TwinsUK

AF:

0.120

AC:

444

ALSPAC

AF:

0.111

AC:

429

ESP6500AA

AF:

0.133

AC:

586

ESP6500EA

AF:

0.120

AC:

1036

ExAC

AF:

0.130

AC:

15792

Asia WGS

AF:

0.128

AC:

446

AN:

3478

EpiCase

AF:

0.123

EpiControl

AF:

0.122

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

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

Uncertain

0.35

BayesDel_addAF

Benign

-0.58

BayesDel_noAF

Benign

-0.46

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.26

Eigen

Uncertain

0.26

Eigen_PC

Benign

0.13

FATHMM_MKL

Uncertain

0.93

LIST_S2

Uncertain

0.87

MetaRNN

Benign

0.0020

MetaSVM

Benign

-1.0

MutationAssessor

Pathogenic

3.0

PrimateAI

Benign

0.41

PROVEAN

Uncertain

-3.0

REVEL

Benign

0.28

Sift

Uncertain

0.0090

Sift4G

Uncertain

0.0060

Polyphen

1.0

Vest4

0.22

MutPred

0.61

Gain of catalytic residue at L2153 (P = 0.0325);

MPC

0.46

ClinPred

0.031

GERP RS

0.62

Varity_R

0.30

gMVP

0.62

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.060

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