rs3740168

Positions:

chr10-16906391-G-C

Variant summary

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

The NM_001081.4(CUBN):c.7724C>G(p.Pro2575Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0258 in 1,613,304 control chromosomes in the GnomAD database, including 1,387 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 0.025 ( 148 hom., cov: 32)

Exomes 𝑓: 0.026 ( 1239 hom. )

Consequence

CUBN
NM_001081.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 1.81

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:

CUBN (HGNC:):

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=0.0017643869).

BP6

Variant 10-16906391-G-C is Benign according to our data. Variant chr10-16906391-G-C is described in ClinVar as [Benign]. Clinvar id is 299419.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.128 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.7724C>G	p.Pro2575Arg	missense_variant	50/67	ENST00000377833.10	NP_001072.2	O60494

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
CUBN	ENST00000377833.10 linkuse as main transcript	c.7724C>G	p.Pro2575Arg	missense_variant	50/67	1	NM_001081.4	ENSP00000367064.4	O60494
CUBN	ENST00000648092.1 linkuse as main transcript	n.260C>G		non_coding_transcript_exon_variant	2/4
CUBN	ENST00000649933.1 linkuse as main transcript	n.86C>G		non_coding_transcript_exon_variant	2/5

Frequencies

GnomAD3 genomes

AF:

0.0246

AC:

3745

AN:

152118

Hom.:

148

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00632

Gnomad AMI

AF:

0.0987

Gnomad AMR

AF:

0.0587

Gnomad ASJ

AF:

0.0121

Gnomad EAS

AF:

0.136

Gnomad SAS

AF:

0.100

Gnomad FIN

AF:

0.0101

Gnomad MID

AF:

0.0316

Gnomad NFE

AF:

0.0159

Gnomad OTH

AF:

0.0316

GnomAD3 exomes

AF:

0.0447

AC:

11231

AN:

251168

Hom.:

543

AF XY:

0.0443

AC XY:

6014

AN XY:

135762

show subpopulations

Gnomad AFR exome

AF:

0.00622

Gnomad AMR exome

AF:

0.0972

Gnomad ASJ exome

AF:

0.0155

Gnomad EAS exome

AF:

0.136

Gnomad SAS exome

AF:

0.0932

Gnomad FIN exome

AF:

0.0102

Gnomad NFE exome

AF:

0.0160

Gnomad OTH exome

AF:

0.0354

GnomAD4 exome

AF:

0.0260

AC:

37915

AN:

1461068

Hom.:

1239

Cov.:

AF XY:

0.0274

AC XY:

19932

AN XY:

726896

show subpopulations

Gnomad4 AFR exome

AF:

0.00616

Gnomad4 AMR exome

AF:

0.0910

Gnomad4 ASJ exome

AF:

0.0139

Gnomad4 EAS exome

AF:

0.130

Gnomad4 SAS exome

AF:

0.0919

Gnomad4 FIN exome

AF:

0.0102

Gnomad4 NFE exome

AF:

0.0157

Gnomad4 OTH exome

AF:

0.0319

GnomAD4 genome

AF:

0.0246

AC:

3745

AN:

152236

Hom.:

148

Cov.:

AF XY:

0.0269

AC XY:

2002

AN XY:

74444

show subpopulations

Gnomad4 AFR

AF:

0.00638

Gnomad4 AMR

AF:

0.0587

Gnomad4 ASJ

AF:

0.0121

Gnomad4 EAS

AF:

0.136

Gnomad4 SAS

AF:

0.100

Gnomad4 FIN

AF:

0.0101

Gnomad4 NFE

AF:

0.0159

Gnomad4 OTH

AF:

0.0313

Alfa

AF:

0.0196

Hom.:

Bravo

AF:

0.0289

TwinsUK

AF:

0.0175

AC:

ALSPAC

AF:

0.0179

AC:

ESP6500AA

AF:

0.00704

AC:

ESP6500EA

AF:

0.0148

AC:

127

ExAC

AF:

0.0420

AC:

5103

Asia WGS

AF:

0.102

AC:

354

AN:

3478

EpiCase

AF:

0.0200

EpiControl

AF:

0.0206

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 03, 2020	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 02, 2023	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

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 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. -

Imerslund-Grasbeck syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 30, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.088

BayesDel_addAF

Benign

-0.78

BayesDel_noAF

Benign

-0.77

CADD

Benign

7.6

DANN

Benign

0.49

DEOGEN2

Benign

0.024

Eigen

Benign

-1.0

Eigen_PC

Benign

-0.92

FATHMM_MKL

Benign

0.32

LIST_S2

Benign

0.46

MetaRNN

Benign

0.0018

MetaSVM

Benign

-0.96

MutationAssessor

Benign

-1.0

PrimateAI

Benign

0.33

PROVEAN

Benign

0.26

REVEL

Benign

0.059

Sift

Benign

0.20

Sift4G

Uncertain

0.027

Polyphen

0.14

Vest4

0.034

MPC

0.088

ClinPred

0.0061

GERP RS

4.6

Varity_R

0.026

gMVP

0.38

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