10-17071457-C-T

Position:

chr10-17071457-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.2594G>A(p.Ser865Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00947 in 1,613,902 control chromosomes in the GnomAD database, including 84 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 Likely benign (★★).

Frequency

Genomes: 𝑓 0.0073 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0097 ( 83 hom. )

Consequence

CUBN
NM_001081.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.871

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=0.0062994957).

BP6

Variant 10-17071457-C-T is Benign according to our data. Variant chr10-17071457-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 265086.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-17071457-C-T is described in Lovd as [Benign]. Variant chr10-17071457-C-T is described in Lovd as [Likely_pathogenic].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00734 (1117/152208) while in subpopulation NFE AF= 0.0123 (834/68028). AF 95% confidence interval is 0.0116. There are 1 homozygotes in gnomad4. There are 529 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 83 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CUBN	NM_001081.4 linkuse as main transcript	c.2594G>A	p.Ser865Asn	missense_variant	19/67	ENST00000377833.10
CUBN	XM_011519708.3 linkuse as main transcript	c.2594G>A	p.Ser865Asn	missense_variant	19/55

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CUBN	ENST00000377833.10 linkuse as main transcript	c.2594G>A	p.Ser865Asn	missense_variant	19/67	1	NM_001081.4	P1

Frequencies

GnomAD3 genomes

AF:

0.00734

AC:

1117

AN:

152090

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00210

Gnomad AMI

AF:

0.0296

Gnomad AMR

AF:

0.00354

Gnomad ASJ

AF:

0.00720

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00331

Gnomad FIN

AF:

0.00520

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0123

Gnomad OTH

AF:

0.00862

GnomAD3 exomes

AF:

0.00730

AC:

1835

AN:

251288

Hom.:

AF XY:

0.00764

AC XY:

1037

AN XY:

135784

show subpopulations

Gnomad AFR exome

AF:

0.00172

Gnomad AMR exome

AF:

0.00307

Gnomad ASJ exome

AF:

0.00843

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00431

Gnomad FIN exome

AF:

0.00522

Gnomad NFE exome

AF:

0.0116

Gnomad OTH exome

AF:

0.00946

GnomAD4 exome

AF:

0.00969

AC:

14170

AN:

1461694

Hom.:

Cov.:

AF XY:

0.00977

AC XY:

7102

AN XY:

727156

show subpopulations

Gnomad4 AFR exome

AF:

0.00158

Gnomad4 AMR exome

AF:

0.00333

Gnomad4 ASJ exome

AF:

0.00911

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00512

Gnomad4 FIN exome

AF:

0.00618

Gnomad4 NFE exome

AF:

0.0112

Gnomad4 OTH exome

AF:

0.00861

GnomAD4 genome

AF:

0.00734

AC:

1117

AN:

152208

Hom.:

Cov.:

AF XY:

0.00711

AC XY:

529

AN XY:

74422

show subpopulations

Gnomad4 AFR

AF:

0.00210

Gnomad4 AMR

AF:

0.00353

Gnomad4 ASJ

AF:

0.00720

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00332

Gnomad4 FIN

AF:

0.00520

Gnomad4 NFE

AF:

0.0123

Gnomad4 OTH

AF:

0.00853

Alfa

AF:

0.0106

Hom.:

Bravo

AF:

0.00716

TwinsUK

AF:

0.00809

AC:

ALSPAC

AF:

0.0112

AC:

ESP6500AA

AF:

0.00204

AC:

ESP6500EA

AF:

0.0117

AC:

101

ExAC

AF:

0.00745

AC:

904

Asia WGS

AF:

0.00491

AC:

AN:

3478

EpiCase

AF:

0.0103

EpiControl

AF:

0.00942

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 13, 2023	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 29, 2021	Previously reported as either a pathogenic variant associated with inherited cobalamin (vitamin B12) malabsorption, or in linkage disequilibrium with an undetected CUBN pathogenic variant (Tanner et al., 2012); Identified in a patient with methylmalonic acidemia and not considered to be pathogenic (Pupavac et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 22929189, 26827111, 31462756, 33111339) -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	CUBN: BP4, BS2 -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Jan 24, 2018

- -

Imerslund-Grasbeck syndrome type 1

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

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). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

Imerslund-Grasbeck syndrome

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 22, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.074

BayesDel_addAF

Benign

-0.74

BayesDel_noAF

Benign

-0.83

CADD

Benign

0.29

DANN

Benign

0.87

DEOGEN2

Benign

0.026

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.031

LIST_S2

Benign

0.50

MetaRNN

Benign

0.0063

MetaSVM

Benign

-0.98

MutationAssessor

Benign

0.69

MutationTaster

Benign

1.0

PrimateAI

Benign

0.32

PROVEAN

Benign

0.38

REVEL

Benign

0.062

Sift

Benign

0.54

Sift4G

Benign

0.58

Polyphen

0.0070

Vest4

0.66

MVP

0.23

MPC

0.077

ClinPred

0.0011

GERP RS

-4.3

Varity_R

0.051

gMVP

0.20

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