10-16877053-T-C

Position:

chr10-16877053-T-C

Variant summary

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

The NM_001081.4(CUBN):c.8950A>G(p.Ile2984Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0973 in 1,613,908 control chromosomes in the GnomAD database, including 8,352 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.078 ( 551 hom., cov: 32)

Exomes 𝑓: 0.099 ( 7801 hom. )

Consequence

CUBN
NM_001081.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 1.65

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=0.0022598207).

BP6

Variant 10-16877053-T-C is Benign according to our data. Variant chr10-16877053-T-C is described in ClinVar as [Benign]. Clinvar id is 299389.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.117 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
CUBN	NM_001081.4 linkuse as main transcript	c.8950A>G	p.Ile2984Val	missense_variant	57/67	ENST00000377833.10
CUBN	XM_011519709.3 linkuse as main transcript	c.4936A>G	p.Ile1646Val	missense_variant	31/41
CUBN	XM_011519710.3 linkuse as main transcript	c.4912A>G	p.Ile1638Val	missense_variant	31/41
CUBN	XM_011519711.4 linkuse as main transcript	c.4792A>G	p.Ile1598Val	missense_variant	30/40

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CUBN	ENST00000377833.10 linkuse as main transcript	c.8950A>G	p.Ile2984Val	missense_variant	57/67	1	NM_001081.4	P1

Frequencies

GnomAD3 genomes

AF:

0.0785

AC:

11937

AN:

152038

Hom.:

550

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0303

Gnomad AMI

AF:

0.123

Gnomad AMR

AF:

0.0801

Gnomad ASJ

AF:

0.150

Gnomad EAS

AF:

0.00174

Gnomad SAS

AF:

0.126

Gnomad FIN

AF:

0.0783

Gnomad MID

AF:

0.114

Gnomad NFE

AF:

0.105

Gnomad OTH

AF:

0.0934

GnomAD3 exomes

AF:

0.0893

AC:

22381

AN:

250742

Hom.:

1211

AF XY:

0.0931

AC XY:

12627

AN XY:

135596

show subpopulations

Gnomad AFR exome

AF:

0.0295

Gnomad AMR exome

AF:

0.0723

Gnomad ASJ exome

AF:

0.141

Gnomad EAS exome

AF:

0.00109

Gnomad SAS exome

AF:

0.132

Gnomad FIN exome

AF:

0.0757

Gnomad NFE exome

AF:

0.103

Gnomad OTH exome

AF:

0.0987

GnomAD4 exome

AF:

0.0993

AC:

145165

AN:

1461752

Hom.:

7801

Cov.:

AF XY:

0.101

AC XY:

73143

AN XY:

727184

show subpopulations

Gnomad4 AFR exome

AF:

0.0282

Gnomad4 AMR exome

AF:

0.0729

Gnomad4 ASJ exome

AF:

0.138

Gnomad4 EAS exome

AF:

0.000932

Gnomad4 SAS exome

AF:

0.133

Gnomad4 FIN exome

AF:

0.0793

Gnomad4 NFE exome

AF:

0.103

Gnomad4 OTH exome

AF:

0.0970

GnomAD4 genome

AF:

0.0784

AC:

11933

AN:

152156

Hom.:

551

Cov.:

AF XY:

0.0766

AC XY:

5698

AN XY:

74370

show subpopulations

Gnomad4 AFR

AF:

0.0303

Gnomad4 AMR

AF:

0.0800

Gnomad4 ASJ

AF:

0.150

Gnomad4 EAS

AF:

0.00174

Gnomad4 SAS

AF:

0.125

Gnomad4 FIN

AF:

0.0783

Gnomad4 NFE

AF:

0.105

Gnomad4 OTH

AF:

0.0915

Alfa

AF:

0.0997

Hom.:

2029

Bravo

AF:

0.0749

TwinsUK

AF:

0.110

AC:

407

ALSPAC

AF:

0.0999

AC:

385

ESP6500AA

AF:

0.0336

AC:

148

ESP6500EA

AF:

0.103

AC:

889

ExAC

AF:

0.0900

AC:

10930

Asia WGS

AF:

0.0600

AC:

210

AN:

3478

EpiCase

AF:

0.108

EpiControl

AF:

0.107

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 07, 2018	This variant is associated with the following publications: (PMID: 24052458, 21355061, 23114252) -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -

Imerslund-Grasbeck syndrome type 1

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Mar 06, 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. -

Imerslund-Grasbeck syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 30, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.67

BayesDel_noAF

Benign

-0.63

CADD

Benign

DANN

Benign

0.81

DEOGEN2

Benign

0.036

Eigen

Benign

-0.44

Eigen_PC

Benign

-0.27

FATHMM_MKL

Benign

0.71

LIST_S2

Benign

0.55

MetaRNN

Benign

0.0023

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.97

MutationTaster

Benign

0.41

PrimateAI

Benign

0.36

PROVEAN

Benign

-0.38

REVEL

Benign

0.12

Sift

Benign

0.41

Sift4G

Benign

0.099

Polyphen

0.016

Vest4

0.052

MPC

0.074

ClinPred

0.0020

GERP RS

3.6

Varity_R

0.038

gMVP

0.42

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