rs1801225

Positions:

• chr10-17071564-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001081.4(CUBN):​c.2487G>A​(p.Ser829=) 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

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]

ACMG classification

Verdict is Benign. Variant got -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 id is 299504.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-17071564-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.534 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CUBN	NM_001081.4	c.2487G>A	p.Ser829=	synonymous_variant	19/67	ENST00000377833.10	NP_001072.2
CUBN	XM_011519708.3	c.2487G>A	p.Ser829=	synonymous_variant	19/55		XP_011518010.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CUBN	ENST00000377833.10	c.2487G>A	p.Ser829=	synonymous_variant	19/67	1	NM_001081.4	ENSP00000367064	P1

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

GnomAD3 exomes AF: 0.437 AC: 109668 AN: 250838 Hom.: 25365 AF XY: 0.439 AC XY: 59504 AN XY: 135578

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 SAS exome AF: 0.467

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

Gnomad4 AFR exome AF: 0.0964

Gnomad4 AMR exome AF: 0.523

Gnomad4 ASJ exome AF: 0.424

Gnomad4 EAS exome AF: 0.523

Gnomad4 SAS exome AF: 0.463

Gnomad4 FIN exome AF: 0.373

Gnomad4 NFE exome AF: 0.451

Gnomad4 OTH exome AF: 0.435

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

Gnomad4 AFR AF: 0.108

Gnomad4 AMR AF: 0.470

Gnomad4 ASJ AF: 0.431

Gnomad4 EAS AF: 0.551

Gnomad4 SAS AF: 0.459

Gnomad4 FIN AF: 0.357

Gnomad4 NFE AF: 0.453

Gnomad4 OTH AF: 0.393

Alfa AF: 0.428 Hom.: 8661

Bravo AF: 0.352

Asia WGS AF: 0.459 AC: 1592 AN: 3476

EpiCase AF: 0.452

EpiControl AF: 0.449

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Imerslund-Grasbeck syndrome type 1 Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 30, 2021	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 07, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 21, 2016

p.Ser829Ser in exon 19 of CUBN: This variant is not expected to have clinical si gnificance because it does not alter an amino acid residue, is not located withi n the splice consensus sequence, and has been identified in 55.00% (4717/8576) o f East Asian chromosomes by the Exome Aggregation Consortium (ExAC, http://exac. broadinstitute.org; dbSNP rs1801225). -

Imerslund-Grasbeck syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.72
CADD	Benign	0.060
DANN	Benign	0.66

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

Publications

LitVar

Other links and lift over

dbSNP: rs1801225; hg19: chr10-17113563; COSMIC: COSV64710261;