10-16879371-T-C

Variant names:

• chr10-16879371-T-C
• rs780838
• NM_001081.4:c.8906-2274A>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.8906-2274A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.473 in 152,156 control chromosomes in the GnomAD database, including 19,346 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 0.47 (19346 hom., cov: 33)
• Consequence: CUBN NM_001081.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.570
• Publications: 11 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=-0.94).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.603 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CUBN	NM_001081.4	c.8906-2274A>G		intron_variant	Intron 56 of 66	ENST00000377833.10	NP_001072.2
CUBN	XM_011519709.3	c.4892-2274A>G		intron_variant	Intron 30 of 40		XP_011518011.1
CUBN	XM_011519710.3	c.4868-2274A>G		intron_variant	Intron 30 of 40		XP_011518012.1
CUBN	XM_011519711.4	c.4748-2274A>G		intron_variant	Intron 29 of 39		XP_011518013.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CUBN	ENST00000377833.10	c.8906-2274A>G		intron_variant	Intron 56 of 66	1	NM_001081.4	ENSP00000367064.4

Frequencies

GnomAD3 genomes AF: 0.474 AC: 72025 AN: 152038 Hom.: 19357 Cov.: 33

Gnomad AFR AF: 0.209

Gnomad AMI AF: 0.560

Gnomad AMR AF: 0.449

Gnomad ASJ AF: 0.623

Gnomad EAS AF: 0.523

Gnomad SAS AF: 0.525

Gnomad FIN AF: 0.571

Gnomad MID AF: 0.627

Gnomad NFE AF: 0.608

Gnomad OTH AF: 0.504

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

GnomAD4 genome AF: 0.473 AC: 72017 AN: 152156 Hom.: 19346 Cov.: 33 AF XY: 0.473 AC XY: 35205 AN XY: 74384

African (AFR) AF: 0.208 AC: 8657 AN: 41524

American (AMR) AF: 0.448 AC: 6856 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.623 AC: 2162 AN: 3470

East Asian (EAS) AF: 0.522 AC: 2701 AN: 5176

South Asian (SAS) AF: 0.525 AC: 2536 AN: 4826

European-Finnish (FIN) AF: 0.571 AC: 6041 AN: 10576

Middle Eastern (MID) AF: 0.627 AC: 183 AN: 292

European-Non Finnish (NFE) AF: 0.608 AC: 41318 AN: 67982

Other (OTH) AF: 0.499 AC: 1052 AN: 2108

Alfa AF: 0.565 Hom.: 41642

Bravo AF: 0.449

Asia WGS AF: 0.490 AC: 1701 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	1.5
DANN	Benign	0.72
PhyloP100		-0.57
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: rs780838; hg19: chr10-16921370;