rs1801228

chr10-17046007-T-Cchr10-17046007-T-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001081.4(CUBN):c.3417A>G(p.Leu1139=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.044 in 1,613,820 control chromosomes in the GnomAD database, including 3,217 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.036 (227 hom., cov: 31)
  • Exomes 𝑓: 0.045 (2990 hom.)
• Consequence: CUBN NM_001081.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -1.62

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.53).
• BP6: Variant 10-17046007-T-C is Benign according to our data. Variant chr10-17046007-T-C is described in ClinVar as [Benign]. Clinvar id is 299490.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.62 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.213 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CUBN	NM_001081.4	c.3417A>G	p.Leu1139=	synonymous_variant	24/67	ENST00000377833.10
CUBN	XM_011519708.3	c.3417A>G	p.Leu1139=	synonymous_variant	24/55

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CUBN	ENST00000377833.10	c.3417A>G	p.Leu1139=	synonymous_variant	24/67	1	NM_001081.4	P1

Frequencies

GnomAD3 genomes AF: 0.0356 AC: 5411 AN: 152096 Hom.: 227 Cov.: 31

Gnomad AFR AF: 0.00867

Gnomad AMI AF: 0.101

Gnomad AMR AF: 0.0277

Gnomad ASJ AF: 0.0916

Gnomad EAS AF: 0.0218

Gnomad SAS AF: 0.225

Gnomad FIN AF: 0.0516

Gnomad MID AF: 0.104

Gnomad NFE AF: 0.0347

Gnomad OTH AF: 0.0396

GnomAD3 exomes AF: 0.0560 AC: 14073 AN: 251336 Hom.: 856 AF XY: 0.0658 AC XY: 8937 AN XY: 135832

Gnomad AFR exome AF: 0.00978

Gnomad AMR exome AF: 0.0229

Gnomad ASJ exome AF: 0.0882

Gnomad EAS exome AF: 0.0194

Gnomad SAS exome AF: 0.204

Gnomad FIN exome AF: 0.0478

Gnomad NFE exome AF: 0.0377

Gnomad OTH exome AF: 0.0524

GnomAD4 exome AF: 0.0449 AC: 65660 AN: 1461606 Hom.: 2990 Cov.: 31 AF XY: 0.0503 AC XY: 36553 AN XY: 727132

Gnomad4 AFR exome AF: 0.00831

Gnomad4 AMR exome AF: 0.0239

Gnomad4 ASJ exome AF: 0.0905

Gnomad4 EAS exome AF: 0.0195

Gnomad4 SAS exome AF: 0.206

Gnomad4 FIN exome AF: 0.0470

Gnomad4 NFE exome AF: 0.0335

Gnomad4 OTH exome AF: 0.0519

GnomAD4 genome AF: 0.0355 AC: 5404 AN: 152214 Hom.: 227 Cov.: 31 AF XY: 0.0395 AC XY: 2940 AN XY: 74410

Gnomad4 AFR AF: 0.00867

Gnomad4 AMR AF: 0.0277

Gnomad4 ASJ AF: 0.0916

Gnomad4 EAS AF: 0.0218

Gnomad4 SAS AF: 0.224

Gnomad4 FIN AF: 0.0516

Gnomad4 NFE AF: 0.0347

Gnomad4 OTH AF: 0.0411

Alfa AF: 0.0368 Hom.: 82

Bravo AF: 0.0282

Asia WGS AF: 0.0940 AC: 325 AN: 3478

EpiCase AF: 0.0453

EpiControl AF: 0.0452

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Imerslund-Grasbeck syndrome type 1 Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 30, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Nov 01, 2018

- -

Imerslund-Grasbeck syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.53
Cadd	Benign	0.49
Dann	Benign	0.80

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

Publications

LitVar

Other links and lift over

dbSNP: rs1801228; hg19: chr10-17088006; COSMIC: COSV64708530;