rs45551835

Positions:

Variant summary

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

The NM_001081.4(CUBN):c.8741C>T(p.Ala2914Val) variant causes a missense change. The variant allele was found at a frequency of 0.0128 in 1,613,244 control chromosomes in the GnomAD database, including 176 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. A2914A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.010 ( 11 hom., cov: 32)

Exomes 𝑓: 0.013 ( 165 hom. )

Consequence

CUBN
NM_001081.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 5.13

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=0.009418815).

BP6

Variant 10-16890385-G-A is Benign according to our data. Variant chr10-16890385-G-A is described in ClinVar as [Benign]. Clinvar id is 299395.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-16890385-G-A is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.01 (1526/152222) while in subpopulation NFE AF= 0.0145 (989/68022). AF 95% confidence interval is 0.0138. There are 11 homozygotes in gnomad4. There are 695 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 11 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
CUBN	NM_001081.4 linkuse as main transcript	c.8741C>T	p.Ala2914Val	missense_variant	55/67	ENST00000377833.10
CUBN	XM_011519709.3 linkuse as main transcript	c.4727C>T	p.Ala1576Val	missense_variant	29/41
CUBN	XM_011519710.3 linkuse as main transcript	c.4703C>T	p.Ala1568Val	missense_variant	29/41
CUBN	XM_011519711.4 linkuse as main transcript	c.4583C>T	p.Ala1528Val	missense_variant	28/40

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CUBN	ENST00000377833.10 linkuse as main transcript	c.8741C>T	p.Ala2914Val	missense_variant	55/67	1	NM_001081.4	P1

Frequencies

GnomAD3 genomes

AF:

0.0100

AC:

1524

AN:

152104

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00278

Gnomad AMI

AF:

0.0505

Gnomad AMR

AF:

0.0145

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.000386

Gnomad SAS

AF:

0.0135

Gnomad FIN

AF:

0.00584

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0145

Gnomad OTH

AF:

0.0110

GnomAD3 exomes

AF:

0.0125

AC:

3154

AN:

251432

Hom.:

AF XY:

0.0124

AC XY:

1685

AN XY:

135880

show subpopulations

Gnomad AFR exome

AF:

0.00228

Gnomad AMR exome

AF:

0.0264

Gnomad ASJ exome

AF:

0.000794

Gnomad EAS exome

AF:

0.000109

Gnomad SAS exome

AF:

0.0119

Gnomad FIN exome

AF:

0.00735

Gnomad NFE exome

AF:

0.0142

Gnomad OTH exome

AF:

0.0103

GnomAD4 exome

AF:

0.0131

AC:

19120

AN:

1461022

Hom.:

165

Cov.:

AF XY:

0.0130

AC XY:

9481

AN XY:

726852

show subpopulations

Gnomad4 AFR exome

AF:

0.00176

Gnomad4 AMR exome

AF:

0.0243

Gnomad4 ASJ exome

AF:

0.000421

Gnomad4 EAS exome

AF:

0.0000756

Gnomad4 SAS exome

AF:

0.0129

Gnomad4 FIN exome

AF:

0.00947

Gnomad4 NFE exome

AF:

0.0141

Gnomad4 OTH exome

AF:

0.0104

GnomAD4 genome

AF:

0.0100

AC:

1526

AN:

152222

Hom.:

Cov.:

AF XY:

0.00934

AC XY:

695

AN XY:

74426

show subpopulations

Gnomad4 AFR

AF:

0.00277

Gnomad4 AMR

AF:

0.0145

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.000387

Gnomad4 SAS

AF:

0.0137

Gnomad4 FIN

AF:

0.00584

Gnomad4 NFE

AF:

0.0145

Gnomad4 OTH

AF:

0.0109

Alfa

AF:

0.0123

Hom.:

Bravo

AF:

0.0104

TwinsUK

AF:

0.0140

AC:

ALSPAC

AF:

0.0150

AC:

ESP6500AA

AF:

0.00204

AC:

ESP6500EA

AF:

0.0142

AC:

122

ExAC

AF:

0.0120

AC:

1460

Asia WGS

AF:

0.00491

AC:

AN:

3478

EpiCase

AF:

0.0142

EpiControl

AF:

0.0130

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	Apr 07, 2020	This variant is associated with the following publications: (PMID: 30220432) -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 11, 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 22, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.21

BayesDel_addAF

Benign

-0.48

BayesDel_noAF

Benign

-0.44

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.11

Eigen

Pathogenic

0.72

Eigen_PC

Pathogenic

0.68

FATHMM_MKL

Uncertain

0.96

LIST_S2

Benign

0.82

MetaRNN

Benign

0.0094

MetaSVM

Benign

-0.82

MutationAssessor

Uncertain

2.7

MutationTaster

Benign

0.98

PrimateAI

Uncertain

0.54

PROVEAN

Uncertain

-2.5

REVEL

Benign

0.22

Sift

Uncertain

0.011

Sift4G

Uncertain

0.0020

Polyphen

1.0

Vest4

0.29

MPC

0.44

ClinPred

0.019

GERP RS

4.5

Varity_R

0.16

gMVP

0.65

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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