10-16828913-G-T

Position:

chr10-16828913-G-T

Variant summary

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

The NM_001081.4(CUBN):c.10656C>A(p.Asn3552Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0819 in 1,614,018 control chromosomes in the GnomAD database, including 6,257 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. N3552N) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.066 ( 473 hom., cov: 31)

Exomes 𝑓: 0.084 ( 5784 hom. )

Consequence

CUBN
NM_001081.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 2.26

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=0.0049888194).

BP6

Variant 10-16828913-G-T is Benign according to our data. Variant chr10-16828913-G-T is described in ClinVar as [Benign]. Clinvar id is 299358.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.137 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
CUBN	NM_001081.4 linkuse as main transcript	c.10656C>A	p.Asn3552Lys	missense_variant	66/67	ENST00000377833.10
CUBN	XM_011519709.3 linkuse as main transcript	c.6642C>A	p.Asn2214Lys	missense_variant	40/41
CUBN	XM_011519710.3 linkuse as main transcript	c.6618C>A	p.Asn2206Lys	missense_variant	40/41
CUBN	XM_011519711.4 linkuse as main transcript	c.6498C>A	p.Asn2166Lys	missense_variant	39/40

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CUBN	ENST00000377833.10 linkuse as main transcript	c.10656C>A	p.Asn3552Lys	missense_variant	66/67	1	NM_001081.4	P1

Frequencies

GnomAD3 genomes

AF:

0.0661

AC:

10049

AN:

152096

Hom.:

467

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0162

Gnomad AMI

AF:

0.134

Gnomad AMR

AF:

0.0364

Gnomad ASJ

AF:

0.0559

Gnomad EAS

AF:

0.146

Gnomad SAS

AF:

0.131

Gnomad FIN

AF:

0.150

Gnomad MID

AF:

0.0285

Gnomad NFE

AF:

0.0794

Gnomad OTH

AF:

0.0583

GnomAD3 exomes

AF:

0.0874

AC:

21977

AN:

251466

Hom.:

1238

AF XY:

0.0912

AC XY:

12401

AN XY:

135906

show subpopulations

Gnomad AFR exome

AF:

0.0155

Gnomad AMR exome

AF:

0.0301

Gnomad ASJ exome

AF:

0.0621

Gnomad EAS exome

AF:

0.154

Gnomad SAS exome

AF:

0.134

Gnomad FIN exome

AF:

0.145

Gnomad NFE exome

AF:

0.0838

Gnomad OTH exome

AF:

0.0754

GnomAD4 exome

AF:

0.0836

AC:

122206

AN:

1461804

Hom.:

5784

Cov.:

AF XY:

0.0853

AC XY:

62041

AN XY:

727210

show subpopulations

Gnomad4 AFR exome

AF:

0.0130

Gnomad4 AMR exome

AF:

0.0305

Gnomad4 ASJ exome

AF:

0.0628

Gnomad4 EAS exome

AF:

0.114

Gnomad4 SAS exome

AF:

0.132

Gnomad4 FIN exome

AF:

0.141

Gnomad4 NFE exome

AF:

0.0809

Gnomad4 OTH exome

AF:

0.0837

GnomAD4 genome

AF:

0.0661

AC:

10059

AN:

152214

Hom.:

473

Cov.:

AF XY:

0.0703

AC XY:

5232

AN XY:

74388

show subpopulations

Gnomad4 AFR

AF:

0.0162

Gnomad4 AMR

AF:

0.0363

Gnomad4 ASJ

AF:

0.0559

Gnomad4 EAS

AF:

0.146

Gnomad4 SAS

AF:

0.131

Gnomad4 FIN

AF:

0.150

Gnomad4 NFE

AF:

0.0794

Gnomad4 OTH

AF:

0.0658

Alfa

AF:

0.0739

Hom.:

892

Bravo

AF:

0.0541

TwinsUK

AF:

0.0828

AC:

307

ALSPAC

AF:

0.0864

AC:

333

ESP6500AA

AF:

0.0177

AC:

ESP6500EA

AF:

0.0751

AC:

646

ExAC

AF:

0.0886

AC:

10751

EpiCase

AF:

0.0738

EpiControl

AF:

0.0756

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Imerslund-Grasbeck syndrome type 1

Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 30, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	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. -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Aug 10, 2018

- -

Imerslund-Grasbeck syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Benign

-0.79

BayesDel_noAF

Benign

-0.76

CADD

Benign

DANN

Benign

0.64

DEOGEN2

Benign

0.028

Eigen

Benign

-0.30

Eigen_PC

Benign

-0.21

FATHMM_MKL

Uncertain

0.82

LIST_S2

Benign

0.69

MetaRNN

Benign

0.0050

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.1

MutationTaster

Benign

0.53

PrimateAI

Benign

0.29

PROVEAN

Benign

-0.56

REVEL

Benign

0.10

Sift

Benign

0.90

Sift4G

Uncertain

0.059

Polyphen

0.53

Vest4

0.11

MutPred

0.67

Gain of ubiquitination at N3552 (P = 0.0311);

MPC

0.18

ClinPred

0.018

GERP RS

4.0

Varity_R

0.053

gMVP

0.45

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