10-17105522-G-T

Position:

chr10-17105522-G-T

Variant summary

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

The NM_001081.4(CUBN):c.1165C>A(p.Pro389Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.652 in 1,606,728 control chromosomes in the GnomAD database, including 346,564 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.58 ( 26604 hom., cov: 31)

Exomes 𝑓: 0.66 ( 319960 hom. )

Consequence

CUBN
NM_001081.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 3.12

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=4.6242126E-6).

BP6

Variant 10-17105522-G-T is Benign according to our data. Variant chr10-17105522-G-T is described in ClinVar as [Benign]. Clinvar id is 299527.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-17105522-G-T is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.669 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.1165C>A	p.Pro389Thr	missense_variant	11/67	ENST00000377833.10	NP_001072.2	O60494
CUBN	XM_011519708.3 linkuse as main transcript	c.1165C>A	p.Pro389Thr	missense_variant	11/55		XP_011518010.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CUBN	ENST00000377833.10 linkuse as main transcript	c.1165C>A	p.Pro389Thr	missense_variant	11/67	1	NM_001081.4	ENSP00000367064.4		O60494

Frequencies

GnomAD3 genomes

AF:

0.580

AC:

88001

AN:

151784

Hom.:

26589

Cov.:

show subpopulations

Gnomad AFR

AF:

0.409

Gnomad AMI

AF:

0.604

Gnomad AMR

AF:

0.619

Gnomad ASJ

AF:

0.539

Gnomad EAS

AF:

0.671

Gnomad SAS

AF:

0.532

Gnomad FIN

AF:

0.577

Gnomad MID

AF:

0.481

Gnomad NFE

AF:

0.674

Gnomad OTH

AF:

0.567

GnomAD3 exomes

AF:

0.618

AC:

155345

AN:

251400

Hom.:

48889

AF XY:

0.616

AC XY:

83661

AN XY:

135866

show subpopulations

Gnomad AFR exome

AF:

0.402

Gnomad AMR exome

AF:

0.637

Gnomad ASJ exome

AF:

0.530

Gnomad EAS exome

AF:

0.668

Gnomad SAS exome

AF:

0.552

Gnomad FIN exome

AF:

0.592

Gnomad NFE exome

AF:

0.666

Gnomad OTH exome

AF:

0.613

GnomAD4 exome

AF:

0.659

AC:

958980

AN:

1454828

Hom.:

319960

Cov.:

AF XY:

0.655

AC XY:

474204

AN XY:

724130

show subpopulations

Gnomad4 AFR exome

AF:

0.396

Gnomad4 AMR exome

AF:

0.633

Gnomad4 ASJ exome

AF:

0.532

Gnomad4 EAS exome

AF:

0.644

Gnomad4 SAS exome

AF:

0.545

Gnomad4 FIN exome

AF:

0.595

Gnomad4 NFE exome

AF:

0.686

Gnomad4 OTH exome

AF:

0.633

GnomAD4 genome

AF:

0.580

AC:

88054

AN:

151900

Hom.:

26604

Cov.:

AF XY:

0.577

AC XY:

42842

AN XY:

74226

show subpopulations

Gnomad4 AFR

AF:

0.409

Gnomad4 AMR

AF:

0.620

Gnomad4 ASJ

AF:

0.539

Gnomad4 EAS

AF:

0.670

Gnomad4 SAS

AF:

0.531

Gnomad4 FIN

AF:

0.577

Gnomad4 NFE

AF:

0.674

Gnomad4 OTH

AF:

0.566

Alfa

AF:

0.653

Hom.:

55878

Bravo

AF:

0.575

TwinsUK

AF:

0.699

AC:

2591

ALSPAC

AF:

0.690

AC:

2660

ESP6500AA

AF:

0.413

AC:

1819

ESP6500EA

AF:

0.677

AC:

5823

ExAC

AF:

0.614

AC:

74483

Asia WGS

AF:

0.610

AC:

2120

AN:

3478

EpiCase

AF:

0.647

EpiControl

AF:

0.646

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Imerslund-Grasbeck syndrome type 1

Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 30, 2021	- -
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. -

not provided

Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 07, 2018	- -

Imerslund-Grasbeck syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.088

BayesDel_addAF

Benign

-0.73

BayesDel_noAF

Benign

-0.68

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.35

Eigen

Benign

-0.25

Eigen_PC

Benign

-0.24

FATHMM_MKL

Uncertain

0.93

LIST_S2

Benign

0.66

MetaRNN

Benign

0.0000046

MetaSVM

Benign

-0.97

MutationAssessor

Benign

1.6

PrimateAI

Benign

0.30

PROVEAN

Pathogenic

-5.3

REVEL

Benign

0.098

Sift

Uncertain

0.029

Sift4G

Uncertain

0.012

Polyphen

0.67

Vest4

0.14

MPC

0.30

ClinPred

0.051

GERP RS

1.4

Varity_R

0.086

gMVP

0.39

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