10-16977014-T-C

Variant names:

• chr10-16977014-T-C
• rs3012499
• NM_001081.4:c.4695+5470A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001081.4(CUBN):​c.4695+5470A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.873 in 152,180 control chromosomes in the GnomAD database, including 58,900 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.87 (58900 hom., cov: 32)
• Consequence: CUBN NM_001081.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.446
• Publications: 3 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

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.69).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.958 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.4695+5470A>G		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.4695+5470A>G		intron	N/A	ENSP00000367064.4	O60494
	CUBN	ENST00000438254.1	TSL:3	n.261+5470A>G		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.873 AC: 132757 AN: 152062 Hom.: 58877 Cov.: 32

Gnomad AFR AF: 0.728

Gnomad AMI AF: 0.999

Gnomad AMR AF: 0.806

Gnomad ASJ AF: 0.880

Gnomad EAS AF: 0.803

Gnomad SAS AF: 0.867

Gnomad FIN AF: 0.967

Gnomad MID AF: 0.921

Gnomad NFE AF: 0.964

Gnomad OTH AF: 0.896

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

GnomAD4 genome AF: 0.873 AC: 132835 AN: 152180 Hom.: 58900 Cov.: 32 AF XY: 0.870 AC XY: 64754 AN XY: 74416

African (AFR) AF: 0.728 AC: 30196 AN: 41472

American (AMR) AF: 0.805 AC: 12316 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.880 AC: 3054 AN: 3472

East Asian (EAS) AF: 0.803 AC: 4151 AN: 5170

South Asian (SAS) AF: 0.868 AC: 4180 AN: 4818

European-Finnish (FIN) AF: 0.967 AC: 10254 AN: 10608

Middle Eastern (MID) AF: 0.922 AC: 271 AN: 294

European-Non Finnish (NFE) AF: 0.964 AC: 65603 AN: 68026

Other (OTH) AF: 0.897 AC: 1899 AN: 2116

Alfa AF: 0.931 Hom.: 271213

Bravo AF: 0.852

Asia WGS AF: 0.848 AC: 2952 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.69
CADD	Benign	5.0
DANN	Benign	0.95
PhyloP100		0.45
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: rs3012499; hg19: chr10-17019013;