10-16876998-T-C

Position:

chr10-16876998-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.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. 13/20 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

Scores

Clinical Significance

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

Conservation

PhyloP100: 2.83

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=0.0023685992).

BP6

Variant 10-16876998-T-C is Benign according to our data. Variant chr10-16876998-T-C is described in ClinVar as [Benign]. Clinvar id 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CUBN	NM_001081.4 linkuse as main transcript	c.9005A>G	p.Glu3002Gly	missense_variant	57/67	ENST00000377833.10	NP_001072.2	O60494
CUBN	XM_011519709.3 linkuse as main transcript	c.4991A>G	p.Glu1664Gly	missense_variant	31/41		XP_011518011.1
CUBN	XM_011519710.3 linkuse as main transcript	c.4967A>G	p.Glu1656Gly	missense_variant	31/41		XP_011518012.1
CUBN	XM_011519711.4 linkuse as main transcript	c.4847A>G	p.Glu1616Gly	missense_variant	30/40		XP_011518013.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CUBN	ENST00000377833.10 linkuse as main transcript	c.9005A>G	p.Glu3002Gly	missense_variant	57/67	1	NM_001081.4	ENSP00000367064.4		O60494

Frequencies

GnomAD3 genomes

AF:

0.129

AC:

19609

AN:

152024

Hom.:

1442

Cov.:

show subpopulations

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

GnomAD3 exomes

AF:

0.104

AC:

26075

AN:

251364

Hom.:

1630

AF XY:

0.105

AC XY:

14198

AN XY:

135840

show subpopulations

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 SAS exome

AF:

0.141

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.:

AF XY:

0.106

AC XY:

77090

AN XY:

727208

show subpopulations

Gnomad4 AFR exome

AF:

0.212

Gnomad4 AMR exome

AF:

0.0826

Gnomad4 ASJ exome

AF:

0.138

Gnomad4 EAS exome

AF:

0.00126

Gnomad4 SAS exome

AF:

0.141

Gnomad4 FIN exome

AF:

0.0792

Gnomad4 NFE exome

AF:

0.104

Gnomad4 OTH exome

AF:

0.109

GnomAD4 genome

AF:

0.129

AC:

19615

AN:

152142

Hom.:

1445

Cov.:

AF XY:

0.125

AC XY:

9299

AN XY:

74386

show subpopulations

Gnomad4 AFR

AF:

0.204

Gnomad4 AMR

AF:

0.0990

Gnomad4 ASJ

AF:

0.151

Gnomad4 EAS

AF:

0.00213

Gnomad4 SAS

AF:

0.134

Gnomad4 FIN

AF:

0.0788

Gnomad4 NFE

AF:

0.106

Gnomad4 OTH

AF:

0.125

Alfa

AF:

0.107

Hom.:

1438

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

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	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Imerslund-Grasbeck syndrome type 1

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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

Labcorp Genetics (formerly Invitae), Labcorp

Jan 30, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.73

BayesDel_noAF

Benign

-0.68

CADD

Benign

DANN

Benign

0.96

DEOGEN2

Benign

0.15

Eigen

Benign

-0.46

Eigen_PC

Benign

-0.41

FATHMM_MKL

Benign

0.20

LIST_S2

Benign

0.48

MetaRNN

Benign

0.0024

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.6

PrimateAI

Benign

0.37

PROVEAN

Uncertain

-2.8

REVEL

Benign

0.084

Sift

Benign

0.24

Sift4G

Benign

0.12

Polyphen

0.0060

Vest4

0.058

MPC

0.12

ClinPred

0.012

GERP RS

5.8

Varity_R

0.22

gMVP

0.55

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