rs41289311

chr10-17088200-G-Achr10-17088200-G-C

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.1911C>T(p.Leu637=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0428 in 1,612,820 control chromosomes in the GnomAD database, including 2,835 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.035 (204 hom., cov: 31)
  • Exomes 𝑓: 0.044 (2631 hom.)
• Consequence: CUBN NM_001081.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.343

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=-0.5).
• BP6: Variant 10-17088200-G-A is Benign according to our data. Variant chr10-17088200-G-A is described in ClinVar as [Benign]. Clinvar id is 299519.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.343 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.193 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CUBN	NM_001081.4	c.1911C>T	p.Leu637=	synonymous_variant	15/67	ENST00000377833.10
CUBN	XM_011519708.3	c.1911C>T	p.Leu637=	synonymous_variant	15/55

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CUBN	ENST00000377833.10	c.1911C>T	p.Leu637=	synonymous_variant	15/67	1	NM_001081.4	P1

Frequencies

GnomAD3 genomes AF: 0.0354 AC: 5371 AN: 151922 Hom.: 205 Cov.: 31

Gnomad AFR AF: 0.0106

Gnomad AMI AF: 0.100

Gnomad AMR AF: 0.0272

Gnomad ASJ AF: 0.0892

Gnomad EAS AF: 0.0220

Gnomad SAS AF: 0.204

Gnomad FIN AF: 0.0521

Gnomad MID AF: 0.101

Gnomad NFE AF: 0.0347

Gnomad OTH AF: 0.0388

GnomAD3 exomes AF: 0.0536 AC: 13480 AN: 251284 Hom.: 733 AF XY: 0.0627 AC XY: 8512 AN XY: 135800

Gnomad AFR exome AF: 0.0107

Gnomad AMR exome AF: 0.0222

Gnomad ASJ exome AF: 0.0857

Gnomad EAS exome AF: 0.0205

Gnomad SAS exome AF: 0.185

Gnomad FIN exome AF: 0.0478

Gnomad NFE exome AF: 0.0377

Gnomad OTH exome AF: 0.0501

GnomAD4 exome AF: 0.0435 AC: 63583 AN: 1460780 Hom.: 2631 Cov.: 31 AF XY: 0.0484 AC XY: 35154 AN XY: 726762

Gnomad4 AFR exome AF: 0.0116

Gnomad4 AMR exome AF: 0.0232

Gnomad4 ASJ exome AF: 0.0876

Gnomad4 EAS exome AF: 0.0195

Gnomad4 SAS exome AF: 0.188

Gnomad4 FIN exome AF: 0.0470

Gnomad4 NFE exome AF: 0.0332

Gnomad4 OTH exome AF: 0.0497

GnomAD4 genome AF: 0.0353 AC: 5367 AN: 152040 Hom.: 204 Cov.: 31 AF XY: 0.0389 AC XY: 2894 AN XY: 74306

Gnomad4 AFR AF: 0.0107

Gnomad4 AMR AF: 0.0272

Gnomad4 ASJ AF: 0.0892

Gnomad4 EAS AF: 0.0221

Gnomad4 SAS AF: 0.203

Gnomad4 FIN AF: 0.0521

Gnomad4 NFE AF: 0.0347

Gnomad4 OTH AF: 0.0388

Alfa AF: 0.0329 Hom.: 72

Bravo AF: 0.0287

Asia WGS AF: 0.0760 AC: 264 AN: 3478

EpiCase AF: 0.0451

EpiControl AF: 0.0446

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 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. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Oct 31, 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	-0.50
Cadd	Benign	9.1
Dann	Benign	0.62

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs41289311; hg19: chr10-17130199; COSMIC: COSV64708533;