10-17091684-T-C

Variant names:

• chr10-17091684-T-C
• rs1996316
• NM_001081.4:c.1766-3339A>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.1766-3339A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.332 in 152,104 control chromosomes in the GnomAD database, including 10,191 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 0.33 (10191 hom., cov: 32)
• Consequence: CUBN NM_001081.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.327
• 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=-0.9).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.511 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CUBN	NM_001081.4	MANE Select	c.1766-3339A>G		intron	N/A	NP_001072.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CUBN	ENST00000377833.10	TSL:1 MANE Select	c.1766-3339A>G		intron	N/A	ENSP00000367064.4

Frequencies

GnomAD3 genomes AF: 0.332 AC: 50462 AN: 151986 Hom.: 10175 Cov.: 32

Gnomad AFR AF: 0.0937

Gnomad AMI AF: 0.275

Gnomad AMR AF: 0.463

Gnomad ASJ AF: 0.383

Gnomad EAS AF: 0.528

Gnomad SAS AF: 0.448

Gnomad FIN AF: 0.347

Gnomad MID AF: 0.417

Gnomad NFE AF: 0.419

Gnomad OTH AF: 0.371

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

GnomAD4 genome AF: 0.332 AC: 50486 AN: 152104 Hom.: 10191 Cov.: 32 AF XY: 0.338 AC XY: 25111 AN XY: 74356

African (AFR) AF: 0.0935 AC: 3883 AN: 41534

American (AMR) AF: 0.465 AC: 7094 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.383 AC: 1329 AN: 3468

East Asian (EAS) AF: 0.527 AC: 2725 AN: 5170

South Asian (SAS) AF: 0.449 AC: 2163 AN: 4822

European-Finnish (FIN) AF: 0.347 AC: 3669 AN: 10564

Middle Eastern (MID) AF: 0.421 AC: 123 AN: 292

European-Non Finnish (NFE) AF: 0.419 AC: 28463 AN: 67962

Other (OTH) AF: 0.373 AC: 786 AN: 2108

Alfa AF: 0.401 Hom.: 21420

Bravo AF: 0.329

Asia WGS AF: 0.450 AC: 1560 AN: 3474

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.76
DANN	Benign	0.50
PhyloP100		-0.33
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: rs1996316; hg19: chr10-17133683;