rs2271460

chr10-16919996-A-C

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.6788T>G(p.Phe2263Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0108 in 1,613,874 control chromosomes in the GnomAD database, including 473 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.011 (37 hom., cov: 32)
  • Exomes 𝑓: 0.011 (436 hom.)
• Consequence: CUBN NM_001081.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 7.80

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 (MetaRNN=0.0049438477).
• BP6: Variant 10-16919996-A-C is Benign according to our data. Variant chr10-16919996-A-C is described in ClinVar as [Benign]. Clinvar id is 299434.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0733 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CUBN	NM_001081.4	c.6788T>G	p.Phe2263Cys	missense_variant	44/67	ENST00000377833.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CUBN	ENST00000377833.10	c.6788T>G	p.Phe2263Cys	missense_variant	44/67	1	NM_001081.4	P1

Frequencies

GnomAD3 genomes AF: 0.0108 AC: 1646 AN: 152204 Hom.: 37 Cov.: 32

Gnomad AFR AF: 0.0110

Gnomad AMI AF: 0.00658

Gnomad AMR AF: 0.0113

Gnomad ASJ AF: 0.00317

Gnomad EAS AF: 0.0451

Gnomad SAS AF: 0.0806

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.00501

Gnomad OTH AF: 0.0134

GnomAD3 exomes AF: 0.0172 AC: 4335 AN: 251342 Hom.: 159 AF XY: 0.0200 AC XY: 2712 AN XY: 135836

Gnomad AFR exome AF: 0.0113

Gnomad AMR exome AF: 0.00721

Gnomad ASJ exome AF: 0.00605

Gnomad EAS exome AF: 0.0418

Gnomad SAS exome AF: 0.0780

Gnomad FIN exome AF: 0.000185

Gnomad NFE exome AF: 0.00526

Gnomad OTH exome AF: 0.0134

GnomAD4 exome AF: 0.0108 AC: 15758 AN: 1461552 Hom.: 436 Cov.: 32 AF XY: 0.0128 AC XY: 9315 AN XY: 727092

Gnomad4 AFR exome AF: 0.0121

Gnomad4 AMR exome AF: 0.00740

Gnomad4 ASJ exome AF: 0.00601

Gnomad4 EAS exome AF: 0.0498

Gnomad4 SAS exome AF: 0.0767

Gnomad4 FIN exome AF: 0.000281

Gnomad4 NFE exome AF: 0.00463

Gnomad4 OTH exome AF: 0.0143

GnomAD4 genome AF: 0.0108 AC: 1645 AN: 152322 Hom.: 37 Cov.: 32 AF XY: 0.0122 AC XY: 911 AN XY: 74494

Gnomad4 AFR AF: 0.0111

Gnomad4 AMR AF: 0.0113

Gnomad4 ASJ AF: 0.00317

Gnomad4 EAS AF: 0.0453

Gnomad4 SAS AF: 0.0798

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00501

Gnomad4 OTH AF: 0.0133

Alfa AF: 0.00695 Hom.: 3

Bravo AF: 0.00994

TwinsUK AF: 0.00512 AC: 19

ALSPAC AF: 0.00597 AC: 23

ESP6500AA AF: 0.0125 AC: 55

ESP6500EA AF: 0.00442 AC: 38

ExAC AF: 0.0184 AC: 2228

Asia WGS AF: 0.0560 AC: 195 AN: 3478

EpiCase AF: 0.00725

EpiControl AF: 0.00747

ClinVar

Significance: Benign

Submissions summary: Benign:5

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:2

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 02, 2023	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 22, 2019	This variant is associated with the following publications: (PMID: 30626930) -

Imerslund-Grasbeck syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 30, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.25
Cadd	Uncertain	25
Dann	Uncertain	0.99
DEOGEN2	Benign	0.40	T
Eigen	Pathogenic	0.84
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.66	T
MetaRNN	Benign	0.0049	T
MetaSVM	Uncertain	-0.068	T
MutationAssessor	Pathogenic	4.6	H
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.60	T
PROVEAN	Pathogenic	-7.3	D
REVEL	Uncertain	0.49
Sift	Uncertain	0.0020	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.36
MPC		0.53
ClinPred		0.061	T
GERP RS		5.1
Varity_R		0.55
gMVP		0.88

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: rs2271460; hg19: chr10-16961995; COSMIC: COSV64716606;