rs45619139

Variant names:

• chr10-16898847-C-G
• rs45619139
• NM_001081.4:c.8598+149G>C

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.8598+149G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0898 in 683,108 control chromosomes in the GnomAD database, including 3,206 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.078 (547 hom., cov: 32)
  • Exomes 𝑓: 0.093 (2659 hom.)
• Consequence: CUBN NM_001081.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.515
• Publications: 7 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: Laboratory for Molecular Medicine, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• proteinuria, chronic benign

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

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000296126 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 10-16898847-C-G is Benign according to our data. Variant chr10-16898847-C-G is described in ClinVar as Benign. ClinVar VariationId is 1294111.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.107 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001081.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CUBN	NM_001081.4	MANE Select	c.8598+149G>C		intron	N/A	NP_001072.2	O60494

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CUBN	ENST00000377833.10	TSL:1 MANE Select	c.8598+149G>C		intron	N/A	ENSP00000367064.4	O60494
	ENSG00000296126	ENST00000736661.1		n.195+6213C>G		intron	N/A
	ENSG00000296126	ENST00000736662.1		n.100+7236C>G		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.0779 AC: 11850 AN: 152122 Hom.: 546 Cov.: 32

Gnomad AFR AF: 0.0294

Gnomad AMI AF: 0.217

Gnomad AMR AF: 0.0761

Gnomad ASJ AF: 0.143

Gnomad EAS AF: 0.00173

Gnomad SAS AF: 0.115

Gnomad FIN AF: 0.0801

Gnomad MID AF: 0.120

Gnomad NFE AF: 0.105

Gnomad OTH AF: 0.0880

GnomAD4 exome AF: 0.0933 AC: 49504 AN: 530868 Hom.: 2659 AF XY: 0.0950 AC XY: 27186 AN XY: 286084

African (AFR) AF: 0.0304 AC: 436 AN: 14326

American (AMR) AF: 0.0703 AC: 2033 AN: 28920

Ashkenazi Jewish (ASJ) AF: 0.131 AC: 2296 AN: 17504

East Asian (EAS) AF: 0.000713 AC: 23 AN: 32278

South Asian (SAS) AF: 0.123 AC: 6820 AN: 55508

European-Finnish (FIN) AF: 0.0805 AC: 3360 AN: 41722

Middle Eastern (MID) AF: 0.118 AC: 270 AN: 2284

European-Non Finnish (NFE) AF: 0.102 AC: 31603 AN: 309240

Other (OTH) AF: 0.0916 AC: 2663 AN: 29086

GnomAD4 genome AF: 0.0778 AC: 11850 AN: 152240 Hom.: 547 Cov.: 32 AF XY: 0.0768 AC XY: 5715 AN XY: 74442

African (AFR) AF: 0.0296 AC: 1228 AN: 41556

American (AMR) AF: 0.0760 AC: 1162 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.143 AC: 494 AN: 3466

East Asian (EAS) AF: 0.00173 AC: 9 AN: 5190

South Asian (SAS) AF: 0.115 AC: 553 AN: 4818

European-Finnish (FIN) AF: 0.0801 AC: 849 AN: 10596

Middle Eastern (MID) AF: 0.119 AC: 35 AN: 294

European-Non Finnish (NFE) AF: 0.105 AC: 7141 AN: 68012

Other (OTH) AF: 0.0862 AC: 182 AN: 2112

Alfa AF: 0.0920 Hom.: 93

Bravo AF: 0.0741

Asia WGS AF: 0.0570 AC: 200 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.45
DANN	Benign	0.61
PhyloP100		-0.52
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: rs45619139; hg19: chr10-16940846;