10-17105522-G-T

Position:

• chr10-17105522-G-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.1165C>A​(p.Pro389Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.652 in 1,606,728 control chromosomes in the GnomAD database, including 346,564 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.58 (26604 hom., cov: 31)
  • Exomes 𝑓: 0.66 (319960 hom.)
• Consequence: CUBN NM_001081.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 3.12

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=4.6242126E-6).
• BP6: Variant 10-17105522-G-T is Benign according to our data. Variant chr10-17105522-G-T is described in ClinVar as [Benign]. Clinvar id is 299527.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-17105522-G-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.669 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CUBN	NM_001081.4	c.1165C>A	p.Pro389Thr	missense_variant	11/67	ENST00000377833.10
CUBN	XM_011519708.3	c.1165C>A	p.Pro389Thr	missense_variant	11/55

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CUBN	ENST00000377833.10	c.1165C>A	p.Pro389Thr	missense_variant	11/67	1	NM_001081.4	P1

Frequencies

GnomAD3 genomes AF: 0.580 AC: 88001 AN: 151784 Hom.: 26589 Cov.: 31

Gnomad AFR AF: 0.409

Gnomad AMI AF: 0.604

Gnomad AMR AF: 0.619

Gnomad ASJ AF: 0.539

Gnomad EAS AF: 0.671

Gnomad SAS AF: 0.532

Gnomad FIN AF: 0.577

Gnomad MID AF: 0.481

Gnomad NFE AF: 0.674

Gnomad OTH AF: 0.567

GnomAD3 exomes AF: 0.618 AC: 155345 AN: 251400 Hom.: 48889 AF XY: 0.616 AC XY: 83661 AN XY: 135866

Gnomad AFR exome AF: 0.402

Gnomad AMR exome AF: 0.637

Gnomad ASJ exome AF: 0.530

Gnomad EAS exome AF: 0.668

Gnomad SAS exome AF: 0.552

Gnomad FIN exome AF: 0.592

Gnomad NFE exome AF: 0.666

Gnomad OTH exome AF: 0.613

GnomAD4 exome AF: 0.659 AC: 958980 AN: 1454828 Hom.: 319960 Cov.: 37 AF XY: 0.655 AC XY: 474204 AN XY: 724130

Gnomad4 AFR exome AF: 0.396

Gnomad4 AMR exome AF: 0.633

Gnomad4 ASJ exome AF: 0.532

Gnomad4 EAS exome AF: 0.644

Gnomad4 SAS exome AF: 0.545

Gnomad4 FIN exome AF: 0.595

Gnomad4 NFE exome AF: 0.686

Gnomad4 OTH exome AF: 0.633

GnomAD4 genome AF: 0.580 AC: 88054 AN: 151900 Hom.: 26604 Cov.: 31 AF XY: 0.577 AC XY: 42842 AN XY: 74226

Gnomad4 AFR AF: 0.409

Gnomad4 AMR AF: 0.620

Gnomad4 ASJ AF: 0.539

Gnomad4 EAS AF: 0.670

Gnomad4 SAS AF: 0.531

Gnomad4 FIN AF: 0.577

Gnomad4 NFE AF: 0.674

Gnomad4 OTH AF: 0.566

Alfa AF: 0.653 Hom.: 55878

Bravo AF: 0.575

TwinsUK AF: 0.699 AC: 2591

ALSPAC AF: 0.690 AC: 2660

ESP6500AA AF: 0.413 AC: 1819

ESP6500EA AF: 0.677 AC: 5823

ExAC AF: 0.614 AC: 74483

Asia WGS AF: 0.610 AC: 2120 AN: 3478

EpiCase AF: 0.647

EpiControl AF: 0.646

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

Jul 07, 2018

- -

Imerslund-Grasbeck syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.088
BayesDel_addAF	Benign	-0.73	T
BayesDel_noAF	Benign	-0.68
CADD	Benign	17
DANN	Uncertain	0.99
DEOGEN2	Benign	0.35	T
Eigen	Benign	-0.25
Eigen_PC	Benign	-0.24
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.66	T
MetaRNN	Benign	0.0000046	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	1.6	L
MutationTaster	Benign	0.94	P
PrimateAI	Benign	0.30	T
PROVEAN	Pathogenic	-5.3	D
REVEL	Benign	0.098
Sift	Uncertain	0.029	D
Sift4G	Uncertain	0.012	D
Polyphen		0.67	P
Vest4		0.14
MPC		0.30
ClinPred		0.051	T
GERP RS		1.4
Varity_R		0.086
gMVP		0.39

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: rs1801224; hg19: chr10-17147521; COSMIC: COSV64716468;