10-16869750-C-T

Position:

chr10-16869750-C-T

Variant summary

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

The ENST00000377833.10(CUBN):c.9340G>A(p.Gly3114Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00761 in 1,613,950 control chromosomes in the GnomAD database, including 67 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0051 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0079 ( 67 hom. )

Consequence

CUBN
ENST00000377833.10 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 5.42

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=0.018674761).

BP6

Variant 10-16869750-C-T is Benign according to our data. Variant chr10-16869750-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 439584.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-16869750-C-T is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00511 (777/152146) while in subpopulation NFE AF= 0.00916 (623/67992). AF 95% confidence interval is 0.00857. There are 0 homozygotes in gnomad4. There are 374 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 67 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
CUBN	NM_001081.4 linkuse as main transcript	c.9340G>A	p.Gly3114Ser	missense_variant	59/67	ENST00000377833.10	NP_001072.2
CUBN	XM_011519709.3 linkuse as main transcript	c.5326G>A	p.Gly1776Ser	missense_variant	33/41		XP_011518011.1
CUBN	XM_011519710.3 linkuse as main transcript	c.5302G>A	p.Gly1768Ser	missense_variant	33/41		XP_011518012.1
CUBN	XM_011519711.4 linkuse as main transcript	c.5182G>A	p.Gly1728Ser	missense_variant	32/40		XP_011518013.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CUBN	ENST00000377833.10 linkuse as main transcript	c.9340G>A	p.Gly3114Ser	missense_variant	59/67	1	NM_001081.4	ENSP00000367064	P1

Frequencies

GnomAD3 genomes

AF:

0.00511

AC:

777

AN:

152028

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00133

Gnomad AMI

AF:

0.00439

Gnomad AMR

AF:

0.000459

Gnomad ASJ

AF:

0.000865

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00145

Gnomad FIN

AF:

0.00690

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00916

Gnomad OTH

AF:

0.00191

GnomAD3 exomes

AF:

0.00658

AC:

1653

AN:

251308

Hom.:

AF XY:

0.00657

AC XY:

892

AN XY:

135824

show subpopulations

Gnomad AFR exome

AF:

0.00148

Gnomad AMR exome

AF:

0.000954

Gnomad ASJ exome

AF:

0.00179

Gnomad EAS exome

AF:

0.000653

Gnomad SAS exome

AF:

0.00209

Gnomad FIN exome

AF:

0.00984

Gnomad NFE exome

AF:

0.0110

Gnomad OTH exome

AF:

0.00636

GnomAD4 exome

AF:

0.00787

AC:

11511

AN:

1461804

Hom.:

Cov.:

AF XY:

0.00757

AC XY:

5507

AN XY:

727210

show subpopulations

Gnomad4 AFR exome

AF:

0.00158

Gnomad4 AMR exome

AF:

0.000961

Gnomad4 ASJ exome

AF:

0.00184

Gnomad4 EAS exome

AF:

0.000227

Gnomad4 SAS exome

AF:

0.00176

Gnomad4 FIN exome

AF:

0.0101

Gnomad4 NFE exome

AF:

0.00933

Gnomad4 OTH exome

AF:

0.00487

GnomAD4 genome

AF:

0.00511

AC:

777

AN:

152146

Hom.:

Cov.:

AF XY:

0.00503

AC XY:

374

AN XY:

74378

show subpopulations

Gnomad4 AFR

AF:

0.00132

Gnomad4 AMR

AF:

0.000458

Gnomad4 ASJ

AF:

0.000865

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00145

Gnomad4 FIN

AF:

0.00690

Gnomad4 NFE

AF:

0.00916

Gnomad4 OTH

AF:

0.00189

Alfa

AF:

0.00777

Hom.:

Bravo

AF:

0.00470

TwinsUK

AF:

0.0108

AC:

ALSPAC

AF:

0.00960

AC:

ESP6500AA

AF:

0.000908

AC:

ESP6500EA

AF:

0.00756

AC:

ExAC

AF:

0.00735

AC:

892

Asia WGS

AF:

0.000867

AC:

AN:

3476

EpiCase

AF:

0.00611

EpiControl

AF:

0.00676

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	CUBN: BP4, BS2 -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 13, 2022	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 13, 2020	- -

Imerslund-Grasbeck syndrome type 1

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

May 15, 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

Labcorp Genetics (formerly Invitae), Labcorp

Jan 18, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.13

BayesDel_noAF

Uncertain

0.050

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.34

Eigen

Pathogenic

0.74

Eigen_PC

Uncertain

0.66

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.90

MetaRNN

Benign

0.019

MetaSVM

Uncertain

0.012

MutationAssessor

Uncertain

2.9

MutationTaster

Benign

1.0

PrimateAI

Benign

0.44

PROVEAN

Pathogenic

-5.8

REVEL

Uncertain

0.50

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.85

MVP

0.87

MPC

0.40

ClinPred

0.018

GERP RS

5.7

Varity_R

0.83

gMVP

0.91

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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