10-16869750-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001081.4(CUBN):c.9340G>A(p.Gly3114Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00761 in 1,613,950 control chromosomes in the GnomAD database, including 67 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0051 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0079 ( 67 hom. )

Consequence

CUBN
NM_001081.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 5.42

Publications

10 publications found

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 Gene-Disease associations (from GenCC):

Imerslund-Grasbeck syndrome type 1
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Laboratory for Molecular Medicine
proteinuria, chronic benign
Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
Imerslund-Grasbeck syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

CUBN links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.018674761).

BP6

Variant 10-16869750-C-T is Benign according to our data. Variant chr10-16869750-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 439584.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 = 0.00511 (777/152146) while in subpopulation NFE AF = 0.00916 (623/67992). AF 95% confidence interval is 0.00857. There are 0 homozygotes in GnomAd4. There are 374 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 67 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CUBN	NM_001081.4 link	c.9340G>A	p.Gly3114Ser	missense_variant	Exon 59 of 67	ENST00000377833.10	NP_001072.2	O60494
CUBN	XM_011519709.3 link	c.5326G>A	p.Gly1776Ser	missense_variant	Exon 33 of 41		XP_011518011.1
CUBN	XM_011519710.3 link	c.5302G>A	p.Gly1768Ser	missense_variant	Exon 33 of 41		XP_011518012.1
CUBN	XM_011519711.4 link	c.5182G>A	p.Gly1728Ser	missense_variant	Exon 32 of 40		XP_011518013.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CUBN	ENST00000377833.10 link	c.9340G>A	p.Gly3114Ser	missense_variant	Exon 59 of 67	1	NM_001081.4	ENSP00000367064.4		O60494

Frequencies

GnomAD3 genomes

AF:

0.00511

AC:

777

AN:

152028

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00133

Gnomad AMI

AF:

0.00439

Gnomad AMR

AF:

0.000459

Gnomad ASJ

AF:

0.000865

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00145

Gnomad FIN

AF:

0.00690

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00916

Gnomad OTH

AF:

0.00191

GnomAD2 exomes

AF:

0.00658

AC:

1653

AN:

251308

AF XY:

0.00657

show subpopulations

Gnomad AFR exome

AF:

0.00148

Gnomad AMR exome

AF:

0.000954

Gnomad ASJ exome

AF:

0.00179

Gnomad EAS exome

AF:

0.000653

Gnomad FIN exome

AF:

0.00984

Gnomad NFE exome

AF:

0.0110

Gnomad OTH exome

AF:

0.00636

GnomAD4 exome

AF:

0.00787

AC:

11511

AN:

1461804

Hom.:

Cov.:

AF XY:

0.00757

AC XY:

5507

AN XY:

727210

show subpopulations

African (AFR)

AF:

0.00158

AC:

AN:

33480

American (AMR)

AF:

0.000961

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00184

AC:

AN:

26136

East Asian (EAS)

AF:

0.000227

AC:

AN:

39700

South Asian (SAS)

AF:

0.00176

AC:

152

AN:

86258

European-Finnish (FIN)

AF:

0.0101

AC:

540

AN:

53420

Middle Eastern (MID)

AF:

0.000173

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00933

AC:

10371

AN:

1111926

Other (OTH)

AF:

0.00487

AC:

294

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

Heterozygous variant carriers

646

1292

1938

2584

3230

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

350

700

1050

1400

1750

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00511

AC:

777

AN:

152146

Hom.:

Cov.:

AF XY:

0.00503

AC XY:

374

AN XY:

74378

show subpopulations

African (AFR)

AF:

0.00132

AC:

AN:

41518

American (AMR)

AF:

0.000458

AC:

AN:

15272

Ashkenazi Jewish (ASJ)

AF:

0.000865

AC:

AN:

3470

East Asian (EAS)

AF:

0.000193

AC:

AN:

5174

South Asian (SAS)

AF:

0.00145

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00690

AC:

AN:

10574

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00916

AC:

623

AN:

67992

Other (OTH)

AF:

0.00189

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

119

159

199

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00849

Hom.:

Bravo

AF:

0.00470

TwinsUK

AF:

0.0108

AC:

ALSPAC

AF:

0.00960

AC:

ESP6500AA

AF:

0.000908

AC:

ESP6500EA

AF:

0.00756

AC:

ExAC

AF:

0.00735

AC:

892

Asia WGS

AF:

0.000867

AC:

AN:

3476

EpiCase

AF:

0.00611

EpiControl

AF:

0.00676

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Oct 13, 2020

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 13, 2022

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

CUBN: BP4, BS2 -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Imerslund-Grasbeck syndrome type 1

Benign:1

May 15, 2017

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. -

Imerslund-Grasbeck syndrome

Benign:1

Jan 31, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.13

BayesDel_noAF

Uncertain

0.050

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.34

Eigen

Pathogenic

0.74

Eigen_PC

Uncertain

0.66

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.90

MetaRNN

Benign

0.019

MetaSVM

Uncertain

0.012

MutationAssessor

Uncertain

2.9

PhyloP100

5.4

PrimateAI

Benign

0.44

PROVEAN

Pathogenic

-5.8

REVEL

Uncertain

0.50

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.85

MVP

0.87

MPC

0.40

ClinPred

0.018

GERP RS

5.7

Varity_R

0.83

gMVP

0.91

Mutation Taster

=61/39

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over