rs146027947

Positions:

chr10-16836376-C-T

Variant summary

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

The NM_001081.4(CUBN):c.10039G>A(p.Gly3347Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00228 in 1,613,966 control chromosomes in the GnomAD database, including 47 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0078 ( 16 hom., cov: 32)

Exomes 𝑓: 0.0017 ( 31 hom. )

Consequence

CUBN
NM_001081.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 0.158

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=0.0038042367).

BP6

Variant 10-16836376-C-T is Benign according to our data. Variant chr10-16836376-C-T is described in ClinVar as [Benign]. Clinvar id is 299371.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00777 (1183/152286) while in subpopulation EAS AF= 0.0372 (193/5186). AF 95% confidence interval is 0.0329. There are 16 homozygotes in gnomad4. There are 575 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 16 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
CUBN	NM_001081.4 linkuse as main transcript	c.10039G>A	p.Gly3347Arg	missense_variant	63/67	ENST00000377833.10
CUBN	XM_011519709.3 linkuse as main transcript	c.6025G>A	p.Gly2009Arg	missense_variant	37/41
CUBN	XM_011519710.3 linkuse as main transcript	c.6001G>A	p.Gly2001Arg	missense_variant	37/41
CUBN	XM_011519711.4 linkuse as main transcript	c.5881G>A	p.Gly1961Arg	missense_variant	36/40

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CUBN	ENST00000377833.10 linkuse as main transcript	c.10039G>A	p.Gly3347Arg	missense_variant	63/67	1	NM_001081.4	P1

Frequencies

GnomAD3 genomes

AF:

0.00777

AC:

1182

AN:

152168

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0216

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00301

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.0375

Gnomad SAS

AF:

0.00186

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000323

Gnomad OTH

AF:

0.00718

GnomAD3 exomes

AF:

0.00507

AC:

1272

AN:

250972

Hom.:

AF XY:

0.00424

AC XY:

576

AN XY:

135746

show subpopulations

Gnomad AFR exome

AF:

0.0234

Gnomad AMR exome

AF:

0.00110

Gnomad ASJ exome

AF:

0.0000993

Gnomad EAS exome

AF:

0.0418

Gnomad SAS exome

AF:

0.000849

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000405

Gnomad OTH exome

AF:

0.00245

GnomAD4 exome

AF:

0.00171

AC:

2497

AN:

1461680

Hom.:

Cov.:

AF XY:

0.00160

AC XY:

1166

AN XY:

727166

show subpopulations

Gnomad4 AFR exome

AF:

0.0197

Gnomad4 AMR exome

AF:

0.00132

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.0284

Gnomad4 SAS exome

AF:

0.00122

Gnomad4 FIN exome

AF:

0.0000936

Gnomad4 NFE exome

AF:

0.000252

Gnomad4 OTH exome

AF:

0.00406

GnomAD4 genome

AF:

0.00777

AC:

1183

AN:

152286

Hom.:

Cov.:

AF XY:

0.00772

AC XY:

575

AN XY:

74452

show subpopulations

Gnomad4 AFR

AF:

0.0216

Gnomad4 AMR

AF:

0.00301

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.0372

Gnomad4 SAS

AF:

0.00187

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000323

Gnomad4 OTH

AF:

0.00758

Alfa

AF:

0.00135

Hom.:

Bravo

AF:

0.00880

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000778

AC:

ESP6500AA

AF:

0.0204

AC:

ESP6500EA

AF:

0.000465

AC:

ExAC

AF:

0.00521

AC:

633

Asia WGS

AF:

0.0130

AC:

AN:

3478

EpiCase

AF:

0.000327

EpiControl

AF:

0.000356

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Imerslund-Grasbeck syndrome type 1

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

Imerslund-Grasbeck syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 22, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.075

BayesDel_addAF

Benign

-0.69

BayesDel_noAF

Benign

-0.74

CADD

Benign

3.0

DANN

Benign

0.41

DEOGEN2

Benign

0.060

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.079

LIST_S2

Benign

0.42

MetaRNN

Benign

0.0038

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.6

MutationTaster

Benign

1.0

PrimateAI

Benign

0.22

PROVEAN

Benign

-2.1

REVEL

Benign

0.085

Sift

Benign

0.20

Sift4G

Uncertain

0.014

Polyphen

0.099

Vest4

0.14

MutPred

0.53

Gain of solvent accessibility (P = 0.0023);

MVP

0.32

MPC

0.096

ClinPred

0.0031

GERP RS

-0.40

Varity_R

0.046

gMVP

0.62

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