rs148869805

chr10-17068640-T-C

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001081.4(CUBN):c.2756A>G(p.His919Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00662 in 1,612,972 control chromosomes in the GnomAD database, including 48 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0046 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0068 (46 hom.)
• Consequence: CUBN NM_001081.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:5
• Conservation: PhyloP100: 0.176

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.014198065).
• BP6: Variant 10-17068640-T-C is Benign according to our data. Variant chr10-17068640-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 439581.We mark this variant Likely_benign, oryginal submissions are: {Benign=3, Likely_benign=2, Uncertain_significance=1}. Variant chr10-17068640-T-C is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00459 (697/152016) while in subpopulation NFE AF= 0.00744 (506/67970). AF 95% confidence interval is 0.00691. There are 2 homozygotes in gnomad4. There are 302 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CUBN	NM_001081.4	c.2756A>G	p.His919Arg	missense_variant	20/67	ENST00000377833.10
CUBN	XM_011519708.3	c.2756A>G	p.His919Arg	missense_variant	20/55

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CUBN	ENST00000377833.10	c.2756A>G	p.His919Arg	missense_variant	20/67	1	NM_001081.4	P1

Frequencies

GnomAD3 genomes AF: 0.00460 AC: 699 AN: 151904 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.00157

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00578

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00114

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00746

Gnomad OTH AF: 0.00814

GnomAD3 exomes AF: 0.00402 AC: 1008 AN: 251048 Hom.: 4 AF XY: 0.00397 AC XY: 538 AN XY: 135662

Gnomad AFR exome AF: 0.00105

Gnomad AMR exome AF: 0.00454

Gnomad ASJ exome AF: 0.00199

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.000196

Gnomad FIN exome AF: 0.000601

Gnomad NFE exome AF: 0.00674

Gnomad OTH exome AF: 0.00490

GnomAD4 exome AF: 0.00683 AC: 9984 AN: 1460956 Hom.: 46 Cov.: 32 AF XY: 0.00655 AC XY: 4760 AN XY: 726784

Gnomad4 AFR exome AF: 0.00102

Gnomad4 AMR exome AF: 0.00521

Gnomad4 ASJ exome AF: 0.00126

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000302

Gnomad4 FIN exome AF: 0.000749

Gnomad4 NFE exome AF: 0.00829

Gnomad4 OTH exome AF: 0.00656

GnomAD4 genome AF: 0.00459 AC: 697 AN: 152016 Hom.: 2 Cov.: 32 AF XY: 0.00406 AC XY: 302 AN XY: 74318

Gnomad4 AFR AF: 0.00157

Gnomad4 AMR AF: 0.00577

Gnomad4 ASJ AF: 0.00202

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00114

Gnomad4 NFE AF: 0.00744

Gnomad4 OTH AF: 0.00806

Alfa AF: 0.00682 Hom.: 8

Bravo AF: 0.00539

TwinsUK AF: 0.00836 AC: 31

ALSPAC AF: 0.00960 AC: 37

ESP6500AA AF: 0.00227 AC: 10

ESP6500EA AF: 0.00756 AC: 65

ExAC AF: 0.00390 AC: 473

Asia WGS AF: 0.000289 AC: 1 AN: 3474

EpiCase AF: 0.00889

EpiControl AF: 0.00954

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Feb 04, 2021	The p.His919Arg (rs148869805) has not been reported in the scientific literature or gene specific variant databases. The p.His919Arg is listed in the Genome Aggregation Database (gnomAD) with allele frequency of 0.6 percent (identified in 844 out of 126,288chromosomes) in non-Finnish European population and with overall allele frequency of 0.4 percent (1111/ 276,594 chromosomes) including four homozygotes. Histidine 919 is moderately conserved considering 10 species and mouse has arginine at this position suggesting that the amino acid change may be evolutionary tolerated. Computational prediction programs do not support an impact on the protein (SIFT: tolerated, PolyPhen-2: benign, and MutationTaster: polymorphism). Thus the p.His919Arg is likely to be a benign variant. -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2023	CUBN: BP4, BS2 -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 28, 2020	- -

Imerslund-Grasbeck syndrome type 1 Benign:1

Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

See cases Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein

Feb 03, 2022

ACMG classification criteria: BS1, BS2, BP4 -

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
AlphaMissense	Benign	0.057
BayesDel_addAF	Benign	-0.72	T
BayesDel_noAF	Benign	-0.80
Cadd	Benign	5.7
Dann	Benign	0.79
DEOGEN2	Benign	0.025	T
Eigen	Benign	-0.91
Eigen_PC	Benign	-0.71
FATHMM_MKL	Benign	0.64	D
LIST_S2	Benign	0.62	T
MetaRNN	Benign	0.014	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	-1.5	N
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.78	N
REVEL	Benign	0.12
Sift	Benign	0.50	T
Sift4G	Benign	0.88	T
Polyphen		0.0020	B
Vest4		0.11
MVP		0.25
MPC		0.10
ClinPred		0.0022	T
GERP RS		-3.0
Varity_R		0.059
gMVP		0.46

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs148869805; hg19: chr10-17110639; COSMIC: COSV64713513;