rs17343073

Variant names:

• chr10-16890197-A-T
• rs17343073
• NM_001081.4:c.8755+174T>A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001081.4(CUBN):​c.8755+174T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0818 in 152,044 control chromosomes in the GnomAD database, including 563 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.082 (563 hom., cov: 31)
• Consequence: CUBN NM_001081.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.694
• Publications: 5 publications found

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 Gene-Disease associations (from GenCC):

• Imerslund-Grasbeck syndrome type 1

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Laboratory for Molecular Medicine
• proteinuria, chronic benign

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• Imerslund-Grasbeck syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BP6: Variant 10-16890197-A-T is Benign according to our data. Variant chr10-16890197-A-T is described in ClinVar as Benign. ClinVar VariationId is 1290271.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.114 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CUBN	NM_001081.4	c.8755+174T>A		intron_variant	Intron 55 of 66	ENST00000377833.10	NP_001072.2
CUBN	XM_011519709.3	c.4741+174T>A		intron_variant	Intron 29 of 40		XP_011518011.1
CUBN	XM_011519710.3	c.4717+174T>A		intron_variant	Intron 29 of 40		XP_011518012.1
CUBN	XM_011519711.4	c.4597+174T>A		intron_variant	Intron 28 of 39		XP_011518013.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CUBN	ENST00000377833.10	c.8755+174T>A		intron_variant	Intron 55 of 66	1	NM_001081.4	ENSP00000367064.4

Frequencies

GnomAD3 genomes AF: 0.0819 AC: 12437 AN: 151926 Hom.: 562 Cov.: 31

Gnomad AFR AF: 0.0441

Gnomad AMI AF: 0.123

Gnomad AMR AF: 0.0807

Gnomad ASJ AF: 0.149

Gnomad EAS AF: 0.00174

Gnomad SAS AF: 0.123

Gnomad FIN AF: 0.0781

Gnomad MID AF: 0.117

Gnomad NFE AF: 0.104

Gnomad OTH AF: 0.0931

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.0818 AC: 12433 AN: 152044 Hom.: 563 Cov.: 31 AF XY: 0.0798 AC XY: 5931 AN XY: 74344

African (AFR) AF: 0.0441 AC: 1828 AN: 41446

American (AMR) AF: 0.0806 AC: 1232 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.149 AC: 518 AN: 3472

East Asian (EAS) AF: 0.00175 AC: 9 AN: 5156

South Asian (SAS) AF: 0.122 AC: 588 AN: 4812

European-Finnish (FIN) AF: 0.0781 AC: 826 AN: 10576

Middle Eastern (MID) AF: 0.116 AC: 34 AN: 294

European-Non Finnish (NFE) AF: 0.104 AC: 7094 AN: 67986

Other (OTH) AF: 0.0912 AC: 192 AN: 2106

Alfa AF: 0.0935 Hom.: 101

Bravo AF: 0.0787

Asia WGS AF: 0.0590 AC: 206 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Sep 07, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.18
DANN	Benign	0.43
PhyloP100		-0.69
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs17343073; hg19: chr10-16932196;