rs1276721

Variant names:

• chr10-16930264-G-C
• rs1276721
• NM_001081.4:c.6125-1961C>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.6125-1961C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.835 in 152,222 control chromosomes in the GnomAD database, including 53,210 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 0.83 (53210 hom., cov: 33)
• Consequence: CUBN NM_001081.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.843
• Publications: 2 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.01).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.957 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CUBN	NM_001081.4	c.6125-1961C>G		intron_variant	Intron 40 of 66	ENST00000377833.10	NP_001072.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CUBN	ENST00000377833.10	c.6125-1961C>G		intron_variant	Intron 40 of 66	1	NM_001081.4	ENSP00000367064.4

Frequencies

GnomAD3 genomes AF: 0.835 AC: 126956 AN: 152104 Hom.: 53171 Cov.: 33

Gnomad AFR AF: 0.890

Gnomad AMI AF: 0.859

Gnomad AMR AF: 0.823

Gnomad ASJ AF: 0.851

Gnomad EAS AF: 0.980

Gnomad SAS AF: 0.861

Gnomad FIN AF: 0.786

Gnomad MID AF: 0.886

Gnomad NFE AF: 0.797

Gnomad OTH AF: 0.843

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

GnomAD4 genome AF: 0.835 AC: 127052 AN: 152222 Hom.: 53210 Cov.: 33 AF XY: 0.835 AC XY: 62150 AN XY: 74418

African (AFR) AF: 0.890 AC: 36962 AN: 41552

American (AMR) AF: 0.823 AC: 12583 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.851 AC: 2954 AN: 3470

East Asian (EAS) AF: 0.980 AC: 5081 AN: 5186

South Asian (SAS) AF: 0.861 AC: 4154 AN: 4824

European-Finnish (FIN) AF: 0.786 AC: 8315 AN: 10580

Middle Eastern (MID) AF: 0.878 AC: 258 AN: 294

European-Non Finnish (NFE) AF: 0.797 AC: 54179 AN: 68002

Other (OTH) AF: 0.845 AC: 1783 AN: 2110

Alfa AF: 0.807 Hom.: 6150

Bravo AF: 0.841

Asia WGS AF: 0.918 AC: 3192 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.49
DANN	Benign	0.65
PhyloP100		-0.84
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: rs1276721; hg19: chr10-16972263;