rs17139378

Variant names:

• chr10-16867590-T-C
• rs17139378
• NM_001081.4:c.9454+2046A>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.9454+2046A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.278 in 152,090 control chromosomes in the GnomAD database, including 6,457 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 0.28 (6457 hom., cov: 32)
• Consequence: CUBN NM_001081.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.04
• Publications: 6 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=-0.86).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.564 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CUBN	NM_001081.4	c.9454+2046A>G		intron_variant	Intron 59 of 66	ENST00000377833.10	NP_001072.2
CUBN	XM_011519709.3	c.5440+2046A>G		intron_variant	Intron 33 of 40		XP_011518011.1
CUBN	XM_011519710.3	c.5416+2046A>G		intron_variant	Intron 33 of 40		XP_011518012.1
CUBN	XM_011519711.4	c.5296+2046A>G		intron_variant	Intron 32 of 39		XP_011518013.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CUBN	ENST00000377833.10	c.9454+2046A>G		intron_variant	Intron 59 of 66	1	NM_001081.4	ENSP00000367064.4

Frequencies

GnomAD3 genomes AF: 0.278 AC: 42245 AN: 151972 Hom.: 6440 Cov.: 32

Gnomad AFR AF: 0.302

Gnomad AMI AF: 0.355

Gnomad AMR AF: 0.391

Gnomad ASJ AF: 0.300

Gnomad EAS AF: 0.582

Gnomad SAS AF: 0.391

Gnomad FIN AF: 0.245

Gnomad MID AF: 0.225

Gnomad NFE AF: 0.210

Gnomad OTH AF: 0.285

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

GnomAD4 genome AF: 0.278 AC: 42304 AN: 152090 Hom.: 6457 Cov.: 32 AF XY: 0.288 AC XY: 21404 AN XY: 74324

African (AFR) AF: 0.302 AC: 12543 AN: 41496

American (AMR) AF: 0.392 AC: 5978 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.300 AC: 1041 AN: 3468

East Asian (EAS) AF: 0.581 AC: 2995 AN: 5152

South Asian (SAS) AF: 0.390 AC: 1882 AN: 4822

European-Finnish (FIN) AF: 0.245 AC: 2595 AN: 10578

Middle Eastern (MID) AF: 0.224 AC: 66 AN: 294

European-Non Finnish (NFE) AF: 0.210 AC: 14266 AN: 67988

Other (OTH) AF: 0.291 AC: 615 AN: 2114

Alfa AF: 0.243 Hom.: 11424

Bravo AF: 0.294

Asia WGS AF: 0.443 AC: 1541 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.44
DANN	Benign	0.52
PhyloP100		-1.0
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: rs17139378; hg19: chr10-16909589;