rs74431427

Positions:

Variant summary

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

The NM_001081.4(CUBN):c.9986C>T(p.Ser3329Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00099 in 1,614,086 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. S3329S) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0052 ( 6 hom., cov: 30)

Exomes 𝑓: 0.00055 ( 5 hom. )

Consequence

CUBN
NM_001081.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 5.47

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=0.009660304).

BP6

Variant 10-16840376-G-A is Benign according to our data. Variant chr10-16840376-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 532212.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-16840376-G-A is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00522 (795/152208) while in subpopulation AFR AF= 0.0179 (743/41524). AF 95% confidence interval is 0.0168. There are 6 homozygotes in gnomad4. There are 373 alleles in male gnomad4 subpopulation. Median coverage is 30. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
CUBN	NM_001081.4 linkuse as main transcript	c.9986C>T	p.Ser3329Leu	missense_variant	62/67	ENST00000377833.10
CUBN	XM_011519709.3 linkuse as main transcript	c.5972C>T	p.Ser1991Leu	missense_variant	36/41
CUBN	XM_011519710.3 linkuse as main transcript	c.5948C>T	p.Ser1983Leu	missense_variant	36/41
CUBN	XM_011519711.4 linkuse as main transcript	c.5828C>T	p.Ser1943Leu	missense_variant	35/40

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CUBN	ENST00000377833.10 linkuse as main transcript	c.9986C>T	p.Ser3329Leu	missense_variant	62/67	1	NM_001081.4	P1
CUBN	ENST00000649135.1 linkuse as main transcript			downstream_gene_variant

Frequencies

GnomAD3 genomes

AF:

0.00522

AC:

794

AN:

152090

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0179

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00216

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000103

Gnomad OTH

AF:

0.00479

GnomAD3 exomes

AF:

0.00135

AC:

340

AN:

251270

Hom.:

AF XY:

0.00100

AC XY:

136

AN XY:

135798

show subpopulations

Gnomad AFR exome

AF:

0.0184

Gnomad AMR exome

AF:

0.000694

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000217

Gnomad SAS exome

AF:

0.000131

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000528

Gnomad OTH exome

AF:

0.000490

GnomAD4 exome

AF:

0.000549

AC:

803

AN:

1461878

Hom.:

Cov.:

AF XY:

0.000472

AC XY:

343

AN XY:

727246

show subpopulations

Gnomad4 AFR exome

AF:

0.0185

Gnomad4 AMR exome

AF:

0.000917

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000101

Gnomad4 SAS exome

AF:

0.000151

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000459

Gnomad4 OTH exome

AF:

0.00116

GnomAD4 genome

AF:

0.00522

AC:

795

AN:

152208

Hom.:

Cov.:

AF XY:

0.00501

AC XY:

373

AN XY:

74432

show subpopulations

Gnomad4 AFR

AF:

0.0179

Gnomad4 AMR

AF:

0.00216

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.000208

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000103

Gnomad4 OTH

AF:

0.00474

Alfa

AF:

0.000885

Hom.:

Bravo

AF:

0.00573

ESP6500AA

AF:

0.0182

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00161

AC:

196

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.000164

EpiControl

AF:

0.0000593

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 15, 2018	This variant is associated with the following publications: (PMID: 31462756) -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Aug 10, 2023	- -

CUBN-related disorder

Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 01, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Imerslund-Grasbeck syndrome type 1

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jul 24, 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). 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

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 06, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.57

BayesDel_noAF

Benign

-0.57

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.15

Eigen

Uncertain

0.25

Eigen_PC

Benign

0.13

FATHMM_MKL

Uncertain

0.88

LIST_S2

Benign

0.72

MetaRNN

Benign

0.0097

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.6

MutationTaster

Benign

1.0

PrimateAI

Benign

0.38

PROVEAN

Uncertain

-3.3

REVEL

Benign

0.22

Sift

Benign

0.12

Sift4G

Pathogenic

0.0010

Polyphen

0.98

Vest4

0.38

MVP

0.62

MPC

0.25

ClinPred

0.045

GERP RS

4.7

Varity_R

0.11

gMVP

0.52

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