rs1801225

Variant names:

• chr10-17071564-C-T
• rs1801225
• NM_001081.4:c.2487G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001081.4(CUBN):​c.2487G>A​(p.Ser829Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.436 in 1,612,952 control chromosomes in the GnomAD database, including 158,344 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.36 (11509 hom., cov: 31)
  • Exomes 𝑓: 0.44 (146835 hom.)
• Consequence: CUBN NM_001081.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -1.74
• Publications: 22 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.72).
• BP6: Variant 10-17071564-C-T is Benign according to our data. Variant chr10-17071564-C-T is described in ClinVar as Benign. ClinVar VariationId is 299504.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.534 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.2487G>A	p.Ser829Ser	synonymous	Exon 19 of 67	NP_001072.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CUBN	ENST00000377833.10	TSL:1 MANE Select	c.2487G>A	p.Ser829Ser	synonymous	Exon 19 of 67	ENSP00000367064.4

Frequencies

GnomAD3 genomes AF: 0.356 AC: 53970 AN: 151804 Hom.: 11497 Cov.: 31

Gnomad AFR AF: 0.109

Gnomad AMI AF: 0.320

Gnomad AMR AF: 0.469

Gnomad ASJ AF: 0.431

Gnomad EAS AF: 0.552

Gnomad SAS AF: 0.459

Gnomad FIN AF: 0.357

Gnomad MID AF: 0.440

Gnomad NFE AF: 0.453

Gnomad OTH AF: 0.391

GnomAD2 exomes AF: 0.437 AC: 109668 AN: 250838 AF XY: 0.439

Gnomad AFR exome AF: 0.101

Gnomad AMR exome AF: 0.529

Gnomad ASJ exome AF: 0.425

Gnomad EAS exome AF: 0.548

Gnomad FIN exome AF: 0.370

Gnomad NFE exome AF: 0.445

Gnomad OTH exome AF: 0.438

GnomAD4 exome AF: 0.444 AC: 648583 AN: 1461032 Hom.: 146835 Cov.: 43 AF XY: 0.445 AC XY: 323652 AN XY: 726820

African (AFR) AF: 0.0964 AC: 3228 AN: 33470

American (AMR) AF: 0.523 AC: 23377 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.424 AC: 11075 AN: 26118

East Asian (EAS) AF: 0.523 AC: 20741 AN: 39686

South Asian (SAS) AF: 0.463 AC: 39945 AN: 86230

European-Finnish (FIN) AF: 0.373 AC: 19873 AN: 53350

Middle Eastern (MID) AF: 0.481 AC: 2774 AN: 5766

European-Non Finnish (NFE) AF: 0.451 AC: 501303 AN: 1111334

Other (OTH) AF: 0.435 AC: 26267 AN: 60370

GnomAD4 genome AF: 0.355 AC: 53987 AN: 151920 Hom.: 11509 Cov.: 31 AF XY: 0.360 AC XY: 26697 AN XY: 74222

African (AFR) AF: 0.108 AC: 4487 AN: 41442

American (AMR) AF: 0.470 AC: 7174 AN: 15248

Ashkenazi Jewish (ASJ) AF: 0.431 AC: 1496 AN: 3470

East Asian (EAS) AF: 0.551 AC: 2839 AN: 5150

South Asian (SAS) AF: 0.459 AC: 2206 AN: 4804

European-Finnish (FIN) AF: 0.357 AC: 3766 AN: 10538

Middle Eastern (MID) AF: 0.435 AC: 128 AN: 294

European-Non Finnish (NFE) AF: 0.453 AC: 30771 AN: 67952

Other (OTH) AF: 0.393 AC: 829 AN: 2112

Alfa AF: 0.418 Hom.: 25955

Bravo AF: 0.352

Asia WGS AF: 0.459 AC: 1592 AN: 3476

EpiCase AF: 0.452

EpiControl AF: 0.449

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Imerslund-Grasbeck syndrome type 1 (2)
-	-	2	not provided (2)
-	-	1	Imerslund-Grasbeck syndrome (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.72
CADD	Benign	0.060
DANN	Benign	0.66
PhyloP100		-1.7
Mutation Taster		=78/22	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1801225; hg19: chr10-17113563; COSMIC: COSV64710261;