10-17068599-T-G

Variant summary

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

The NM_001081.4(CUBN):c.2791+6A>C variant causes a splice donor region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0238 in 1,607,084 control chromosomes in the GnomAD database, including 538 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.021 ( 48 hom., cov: 32)

Exomes 𝑓: 0.024 ( 490 hom. )

Consequence

CUBN
NM_001081.4 splice_donor_region, intron

Scores

Splicing: ADA: 0.0001364

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 0.272

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 (BayesDel_noAF=-0.79).

BP6

Variant 10-17068599-T-G is Benign according to our data. Variant chr10-17068599-T-G is described in ClinVar as [Benign]. Clinvar id is 299499.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.058 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CUBN	NM_001081.4 linkuse as main transcript	c.2791+6A>C		splice_donor_region_variant, intron_variant		ENST00000377833.10
CUBN	XM_011519708.3 linkuse as main transcript	c.2791+6A>C		splice_donor_region_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CUBN	ENST00000377833.10 linkuse as main transcript	c.2791+6A>C		splice_donor_region_variant, intron_variant		1	NM_001081.4	P1

Frequencies

GnomAD3 genomes

AF:

0.0206

AC:

3134

AN:

151898

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00570

Gnomad AMI

AF:

0.0110

Gnomad AMR

AF:

0.0190

Gnomad ASJ

AF:

0.0133

Gnomad EAS

AF:

0.0639

Gnomad SAS

AF:

0.0251

Gnomad FIN

AF:

0.0327

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.0252

Gnomad OTH

AF:

0.0206

GnomAD3 exomes

AF:

0.0244

AC:

6095

AN:

249352

Hom.:

AF XY:

0.0247

AC XY:

3319

AN XY:

134594

show subpopulations

Gnomad AFR exome

AF:

0.00666

Gnomad AMR exome

AF:

0.0121

Gnomad ASJ exome

AF:

0.0141

Gnomad EAS exome

AF:

0.0676

Gnomad SAS exome

AF:

0.0208

Gnomad FIN exome

AF:

0.0311

Gnomad NFE exome

AF:

0.0243

Gnomad OTH exome

AF:

0.0255

GnomAD4 exome

AF:

0.0241

AC:

35072

AN:

1455070

Hom.:

490

Cov.:

AF XY:

0.0242

AC XY:

17497

AN XY:

723874

show subpopulations

Gnomad4 AFR exome

AF:

0.00379

Gnomad4 AMR exome

AF:

0.0114

Gnomad4 ASJ exome

AF:

0.0142

Gnomad4 EAS exome

AF:

0.0511

Gnomad4 SAS exome

AF:

0.0208

Gnomad4 FIN exome

AF:

0.0326

Gnomad4 NFE exome

AF:

0.0242

Gnomad4 OTH exome

AF:

0.0277

GnomAD4 genome

AF:

0.0206

AC:

3130

AN:

152014

Hom.:

Cov.:

AF XY:

0.0206

AC XY:

1534

AN XY:

74288

show subpopulations

Gnomad4 AFR

AF:

0.00569

Gnomad4 AMR

AF:

0.0190

Gnomad4 ASJ

AF:

0.0133

Gnomad4 EAS

AF:

0.0637

Gnomad4 SAS

AF:

0.0245

Gnomad4 FIN

AF:

0.0327

Gnomad4 NFE

AF:

0.0252

Gnomad4 OTH

AF:

0.0208

Alfa

AF:

0.0189

Hom.:

Bravo

AF:

0.0190

Asia WGS

AF:

0.0670

AC:

234

AN:

3476

EpiCase

AF:

0.0243

EpiControl

AF:

0.0222

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

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	Oct 09, 2023	- -

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. -

Imerslund-Grasbeck syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 25, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.79

Cadd

Benign

Dann

Benign

0.58

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00014

dbscSNV1_RF

Benign

0.016

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