rs148869805

Positions:

chr10-17068640-T-C

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_001081.4(CUBN):c.2756A>G(p.His919Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00662 in 1,612,972 control chromosomes in the GnomAD database, including 48 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 Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0046 ( 2 hom., cov: 32)

Exomes 𝑓: 0.0068 ( 46 hom. )

Consequence

CUBN
NM_001081.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:5

Conservation

PhyloP100: 0.176

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 -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.014198065).

BP6

Variant 10-17068640-T-C is Benign according to our data. Variant chr10-17068640-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 439581.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=1, Benign=3}. Variant chr10-17068640-T-C is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00459 (697/152016) while in subpopulation NFE AF= 0.00744 (506/67970). AF 95% confidence interval is 0.00691. There are 2 homozygotes in gnomad4. There are 302 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CUBN	NM_001081.4 linkuse as main transcript	c.2756A>G	p.His919Arg	missense_variant	20/67	ENST00000377833.10
CUBN	XM_011519708.3 linkuse as main transcript	c.2756A>G	p.His919Arg	missense_variant	20/55

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CUBN	ENST00000377833.10 linkuse as main transcript	c.2756A>G	p.His919Arg	missense_variant	20/67	1	NM_001081.4	P1

Frequencies

GnomAD3 genomes

AF:

0.00460

AC:

699

AN:

151904

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00157

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00578

Gnomad ASJ

AF:

0.00202

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00114

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.00746

Gnomad OTH

AF:

0.00814

GnomAD3 exomes

AF:

0.00402

AC:

1008

AN:

251048

Hom.:

AF XY:

0.00397

AC XY:

538

AN XY:

135662

show subpopulations

Gnomad AFR exome

AF:

0.00105

Gnomad AMR exome

AF:

0.00454

Gnomad ASJ exome

AF:

0.00199

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.000196

Gnomad FIN exome

AF:

0.000601

Gnomad NFE exome

AF:

0.00674

Gnomad OTH exome

AF:

0.00490

GnomAD4 exome

AF:

0.00683

AC:

9984

AN:

1460956

Hom.:

Cov.:

AF XY:

0.00655

AC XY:

4760

AN XY:

726784

show subpopulations

Gnomad4 AFR exome

AF:

0.00102

Gnomad4 AMR exome

AF:

0.00521

Gnomad4 ASJ exome

AF:

0.00126

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000302

Gnomad4 FIN exome

AF:

0.000749

Gnomad4 NFE exome

AF:

0.00829

Gnomad4 OTH exome

AF:

0.00656

GnomAD4 genome

AF:

0.00459

AC:

697

AN:

152016

Hom.:

Cov.:

AF XY:

0.00406

AC XY:

302

AN XY:

74318

show subpopulations

Gnomad4 AFR

AF:

0.00157

Gnomad4 AMR

AF:

0.00577

Gnomad4 ASJ

AF:

0.00202

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00114

Gnomad4 NFE

AF:

0.00744

Gnomad4 OTH

AF:

0.00806

Alfa

AF:

0.00682

Hom.:

Bravo

AF:

0.00539

TwinsUK

AF:

0.00836

AC:

ALSPAC

AF:

0.00960

AC:

ESP6500AA

AF:

0.00227

AC:

ESP6500EA

AF:

0.00756

AC:

ExAC

AF:

0.00390

AC:

473

Asia WGS

AF:

0.000289

AC:

AN:

3474

EpiCase

AF:

0.00889

EpiControl

AF:

0.00954

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2023	CUBN: BP4, BS2 -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Feb 04, 2021	The p.His919Arg (rs148869805) has not been reported in the scientific literature or gene specific variant databases. The p.His919Arg is listed in the Genome Aggregation Database (gnomAD) with allele frequency of 0.6 percent (identified in 844 out of 126,288chromosomes) in non-Finnish European population and with overall allele frequency of 0.4 percent (1111/ 276,594 chromosomes) including four homozygotes. Histidine 919 is moderately conserved considering 10 species and mouse has arginine at this position suggesting that the amino acid change may be evolutionary tolerated. Computational prediction programs do not support an impact on the protein (SIFT: tolerated, PolyPhen-2: benign, and MutationTaster: polymorphism). Thus the p.His919Arg is likely to be a benign variant. -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 28, 2020	- -

Imerslund-Grasbeck syndrome type 1

Benign:1

Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

See cases

Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein

Feb 03, 2022

ACMG classification criteria: BS1, BS2, BP4 -

Imerslund-Grasbeck syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.057

BayesDel_addAF

Benign

-0.72

BayesDel_noAF

Benign

-0.80

CADD

Benign

5.7

DANN

Benign

0.79

DEOGEN2

Benign

0.025

Eigen

Benign

-0.91

Eigen_PC

Benign

-0.71

FATHMM_MKL

Benign

0.64

LIST_S2

Benign

0.62

MetaRNN

Benign

0.014

MetaSVM

Benign

-0.93

MutationAssessor

Benign

-1.5

MutationTaster

Benign

1.0

PrimateAI

Benign

0.30

PROVEAN

Benign

-0.78

REVEL

Benign

0.12

Sift

Benign

0.50

Sift4G

Benign

0.88

Polyphen

0.0020

Vest4

0.11

MVP

0.25

MPC

0.10

ClinPred

0.0022

GERP RS

-3.0

Varity_R

0.059

gMVP

0.46

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

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