rs45569534

Variant summary

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

The NM_001081.4(CUBN):c.8902G>C(p.Glu2968Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0194 in 1,612,224 control chromosomes in the GnomAD database, including 381 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.016 ( 34 hom., cov: 33)

Exomes 𝑓: 0.020 ( 347 hom. )

Consequence

CUBN
NM_001081.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 2.38

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=0.00558728).

BP6

Variant 10-16888420-C-G is Benign according to our data. Variant chr10-16888420-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 299392.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0157 (2389/152202) while in subpopulation NFE AF= 0.0228 (1548/67986). AF 95% confidence interval is 0.0218. There are 34 homozygotes in gnomad4. There are 1156 alleles in male gnomad4 subpopulation. This position pass quality control queck.

BS2

High Homozygotes in GnomAd at 34 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
CUBN	NM_001081.4 linkuse as main transcript	c.8902G>C	p.Glu2968Gln	missense_variant	56/67	ENST00000377833.10
CUBN	XM_011519709.3 linkuse as main transcript	c.4888G>C	p.Glu1630Gln	missense_variant	30/41
CUBN	XM_011519710.3 linkuse as main transcript	c.4864G>C	p.Glu1622Gln	missense_variant	30/41
CUBN	XM_011519711.4 linkuse as main transcript	c.4744G>C	p.Glu1582Gln	missense_variant	29/40

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CUBN	ENST00000377833.10 linkuse as main transcript	c.8902G>C	p.Glu2968Gln	missense_variant	56/67	1	NM_001081.4	P1

Frequencies

GnomAD3 genomes

AF:

0.0157

AC:

2390

AN:

152084

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00394

Gnomad AMI

AF:

0.0154

Gnomad AMR

AF:

0.0215

Gnomad ASJ

AF:

0.00288

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.000829

Gnomad FIN

AF:

0.0253

Gnomad MID

AF:

0.0222

Gnomad NFE

AF:

0.0228

Gnomad OTH

AF:

0.0216

GnomAD3 exomes

AF:

0.0151

AC:

3789

AN:

251174

Hom.:

AF XY:

0.0146

AC XY:

1983

AN XY:

135772

show subpopulations

Gnomad AFR exome

AF:

0.00486

Gnomad AMR exome

AF:

0.0146

Gnomad ASJ exome

AF:

0.00338

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.000980

Gnomad FIN exome

AF:

0.0204

Gnomad NFE exome

AF:

0.0228

Gnomad OTH exome

AF:

0.0173

GnomAD4 exome

AF:

0.0198

AC:

28962

AN:

1460022

Hom.:

347

Cov.:

AF XY:

0.0191

AC XY:

13884

AN XY:

726454

show subpopulations

Gnomad4 AFR exome

AF:

0.00350

Gnomad4 AMR exome

AF:

0.0157

Gnomad4 ASJ exome

AF:

0.00379

Gnomad4 EAS exome

AF:

0.0000505

Gnomad4 SAS exome

AF:

0.000696

Gnomad4 FIN exome

AF:

0.0196

Gnomad4 NFE exome

AF:

0.0233

Gnomad4 OTH exome

AF:

0.0175

GnomAD4 genome

AF:

0.0157

AC:

2389

AN:

152202

Hom.:

Cov.:

AF XY:

0.0155

AC XY:

1156

AN XY:

74422

show subpopulations

Gnomad4 AFR

AF:

0.00392

Gnomad4 AMR

AF:

0.0215

Gnomad4 ASJ

AF:

0.00288

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.000829

Gnomad4 FIN

AF:

0.0253

Gnomad4 NFE

AF:

0.0228

Gnomad4 OTH

AF:

0.0213

Alfa

AF:

0.0193

Hom.:

Bravo

AF:

0.0156

TwinsUK

AF:

0.0243

AC:

ALSPAC

AF:

0.0187

AC:

ESP6500AA

AF:

0.00545

AC:

ESP6500EA

AF:

0.0231

AC:

199

ExAC

AF:

0.0154

AC:

1864

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.0200

EpiControl

AF:

0.0222

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 01, 2021	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 22, 2023	- -

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

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.26

BayesDel_addAF

Benign

-0.52

BayesDel_noAF

Benign

-0.50

Cadd

Benign

Dann

Uncertain

0.99

DEOGEN2

Benign

0.28

Eigen

Benign

0.17

Eigen_PC

Uncertain

0.25

FATHMM_MKL

Uncertain

0.85

LIST_S2

Benign

0.74

MetaRNN

Benign

0.0056

MetaSVM

Benign

-0.60

MutationAssessor

Uncertain

2.3

MutationTaster

Benign

0.98

PrimateAI

Benign

0.39

PROVEAN

Uncertain

-2.5

REVEL

Uncertain

0.36

Sift

Benign

0.046

Sift4G

Benign

0.086

Polyphen

0.17

Vest4

0.12

MPC

0.19

ClinPred

0.020

GERP RS

5.9

Varity_R

0.36

gMVP

0.79

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