rs17431655

Variant names:

• chr10-17031577-T-C
• rs17431655
• NM_001081.4:c.4017+9456A>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.4017+9456A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0384 in 152,274 control chromosomes in the GnomAD database, including 217 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 0.038 (217 hom., cov: 33)
• Consequence: CUBN NM_001081.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.79
• Publications: 1 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=-0.96).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.198 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CUBN	NM_001081.4	c.4017+9456A>G		intron_variant	Intron 27 of 66	ENST00000377833.10	NP_001072.2
CUBN	XM_011519708.3	c.4017+9456A>G		intron_variant	Intron 27 of 54		XP_011518010.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CUBN	ENST00000377833.10	c.4017+9456A>G		intron_variant	Intron 27 of 66	1	NM_001081.4	ENSP00000367064.4

Frequencies

GnomAD3 genomes AF: 0.0384 AC: 5843 AN: 152156 Hom.: 217 Cov.: 33

Gnomad AFR AF: 0.0199

Gnomad AMI AF: 0.101

Gnomad AMR AF: 0.0285

Gnomad ASJ AF: 0.0888

Gnomad EAS AF: 0.0219

Gnomad SAS AF: 0.210

Gnomad FIN AF: 0.0526

Gnomad MID AF: 0.104

Gnomad NFE AF: 0.0350

Gnomad OTH AF: 0.0416

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

GnomAD4 genome AF: 0.0384 AC: 5847 AN: 152274 Hom.: 217 Cov.: 33 AF XY: 0.0419 AC XY: 3120 AN XY: 74474

African (AFR) AF: 0.0201 AC: 836 AN: 41554

American (AMR) AF: 0.0284 AC: 435 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0888 AC: 308 AN: 3470

East Asian (EAS) AF: 0.0220 AC: 114 AN: 5184

South Asian (SAS) AF: 0.209 AC: 1005 AN: 4812

European-Finnish (FIN) AF: 0.0526 AC: 559 AN: 10618

Middle Eastern (MID) AF: 0.0952 AC: 28 AN: 294

European-Non Finnish (NFE) AF: 0.0350 AC: 2378 AN: 68018

Other (OTH) AF: 0.0435 AC: 92 AN: 2114

Alfa AF: 0.0343 Hom.: 54

Bravo AF: 0.0322

Asia WGS AF: 0.0940 AC: 325 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	0.076
DANN	Benign	0.29
PhyloP100		-1.8
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: rs17431655; hg19: chr10-17073576;