rs140806389

chr10-16918684-T-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001081.4(CUBN):c.6938A>T(p.Tyr2313Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00116 in 1,613,926 control chromosomes in the GnomAD database, including 53 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0019 (16 hom., cov: 32)
  • Exomes 𝑓: 0.0011 (37 hom.)
• Consequence: CUBN NM_001081.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 2.92

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=0.0066486895).
• BP6: Variant 10-16918684-T-A is Benign according to our data. Variant chr10-16918684-T-A is described in ClinVar as [Benign]. Clinvar id is 299432.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-16918684-T-A is described in Lovd as [Benign]. Variant chr10-16918684-T-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.0019 (290/152268) while in subpopulation EAS AF= 0.0503 (260/5172). AF 95% confidence interval is 0.0453. There are 16 homozygotes in gnomad4. There are 156 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 16 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CUBN	NM_001081.4	c.6938A>T	p.Tyr2313Phe	missense_variant	45/67	ENST00000377833.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CUBN	ENST00000377833.10	c.6938A>T	p.Tyr2313Phe	missense_variant	45/67	1	NM_001081.4	P1

Frequencies

GnomAD3 genomes AF: 0.00192 AC: 292 AN: 152150 Hom.: 16 Cov.: 32

Gnomad AFR AF: 0.000290

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0505

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00288

GnomAD3 exomes AF: 0.00426 AC: 1072 AN: 251350 Hom.: 30 AF XY: 0.00385 AC XY: 523 AN XY: 135842

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.0000579

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0566

Gnomad SAS exome AF: 0.000425

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.00212

GnomAD4 exome AF: 0.00108 AC: 1582 AN: 1461658 Hom.: 37 Cov.: 31 AF XY: 0.00105 AC XY: 762 AN XY: 727128

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.0000671

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0339

Gnomad4 SAS exome AF: 0.000614

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000899

Gnomad4 OTH exome AF: 0.00277

GnomAD4 genome AF: 0.00190 AC: 290 AN: 152268 Hom.: 16 Cov.: 32 AF XY: 0.00210 AC XY: 156 AN XY: 74458

Gnomad4 AFR AF: 0.000289

Gnomad4 AMR AF: 0.000327

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0503

Gnomad4 SAS AF: 0.00145

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00285

Alfa AF: 0.000470 Hom.: 0

Bravo AF: 0.00229

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00423 AC: 514

Asia WGS AF: 0.0170 AC: 59 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Imerslund-Grasbeck syndrome type 1 Benign:1

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

May 06, 2021

- -

Imerslund-Grasbeck syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 25, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.40
Cadd	Uncertain	24
Dann	Uncertain	0.98
DEOGEN2	Benign	0.16	T
Eigen	Uncertain	0.42
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.88	D
MetaRNN	Benign	0.0066	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.77	N
MutationTaster	Benign	0.79	D
PrimateAI	Benign	0.46	T
PROVEAN	Uncertain	-3.0	D
REVEL	Benign	0.14
Sift	Uncertain	0.025	D
Sift4G	Uncertain	0.020	D
Polyphen		0.99	D
Vest4		0.55
MVP		0.46
MPC		0.43
ClinPred		0.038	T
GERP RS		4.5
Varity_R		0.18
gMVP		0.35

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: rs140806389; hg19: chr10-16960683; COSMIC: COSV64715433;