rs3740168

chr10-16906391-G-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.7724C>G(p.Pro2575Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0258 in 1,613,304 control chromosomes in the GnomAD database, including 1,387 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. P2575P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.025 (148 hom., cov: 32)
  • Exomes 𝑓: 0.026 (1239 hom.)
• Consequence: CUBN NM_001081.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 1.81

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=0.0017643869).
• BP6: Variant 10-16906391-G-C is Benign according to our data. Variant chr10-16906391-G-C is described in ClinVar as [Benign]. Clinvar id is 299419.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.128 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CUBN	NM_001081.4	c.7724C>G	p.Pro2575Arg	missense_variant	50/67	ENST00000377833.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CUBN	ENST00000377833.10	c.7724C>G	p.Pro2575Arg	missense_variant	50/67	1	NM_001081.4	P1
CUBN	ENST00000648092.1	n.260C>G		non_coding_transcript_exon_variant	2/4
CUBN	ENST00000649933.1	n.86C>G		non_coding_transcript_exon_variant	2/5

Frequencies

GnomAD3 genomes AF: 0.0246 AC: 3745 AN: 152118 Hom.: 148 Cov.: 32

Gnomad AFR AF: 0.00632

Gnomad AMI AF: 0.0987

Gnomad AMR AF: 0.0587

Gnomad ASJ AF: 0.0121

Gnomad EAS AF: 0.136

Gnomad SAS AF: 0.100

Gnomad FIN AF: 0.0101

Gnomad MID AF: 0.0316

Gnomad NFE AF: 0.0159

Gnomad OTH AF: 0.0316

GnomAD3 exomes AF: 0.0447 AC: 11231 AN: 251168 Hom.: 543 AF XY: 0.0443 AC XY: 6014 AN XY: 135762

Gnomad AFR exome AF: 0.00622

Gnomad AMR exome AF: 0.0972

Gnomad ASJ exome AF: 0.0155

Gnomad EAS exome AF: 0.136

Gnomad SAS exome AF: 0.0932

Gnomad FIN exome AF: 0.0102

Gnomad NFE exome AF: 0.0160

Gnomad OTH exome AF: 0.0354

GnomAD4 exome AF: 0.0260 AC: 37915 AN: 1461068 Hom.: 1239 Cov.: 32 AF XY: 0.0274 AC XY: 19932 AN XY: 726896

Gnomad4 AFR exome AF: 0.00616

Gnomad4 AMR exome AF: 0.0910

Gnomad4 ASJ exome AF: 0.0139

Gnomad4 EAS exome AF: 0.130

Gnomad4 SAS exome AF: 0.0919

Gnomad4 FIN exome AF: 0.0102

Gnomad4 NFE exome AF: 0.0157

Gnomad4 OTH exome AF: 0.0319

GnomAD4 genome AF: 0.0246 AC: 3745 AN: 152236 Hom.: 148 Cov.: 32 AF XY: 0.0269 AC XY: 2002 AN XY: 74444

Gnomad4 AFR AF: 0.00638

Gnomad4 AMR AF: 0.0587

Gnomad4 ASJ AF: 0.0121

Gnomad4 EAS AF: 0.136

Gnomad4 SAS AF: 0.100

Gnomad4 FIN AF: 0.0101

Gnomad4 NFE AF: 0.0159

Gnomad4 OTH AF: 0.0313

Alfa AF: 0.0196 Hom.: 11

Bravo AF: 0.0289

TwinsUK AF: 0.0175 AC: 65

ALSPAC AF: 0.0179 AC: 69

ESP6500AA AF: 0.00704 AC: 31

ESP6500EA AF: 0.0148 AC: 127

ExAC AF: 0.0420 AC: 5103

Asia WGS AF: 0.102 AC: 354 AN: 3478

EpiCase AF: 0.0200

EpiControl AF: 0.0206

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 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:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 03, 2020	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 02, 2023	- -

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	Benign	0.088
BayesDel_addAF	Benign	-0.78	T
BayesDel_noAF	Benign	-0.77
Cadd	Benign	7.6
Dann	Benign	0.49
DEOGEN2	Benign	0.024	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-0.92
FATHMM_MKL	Benign	0.32	N
LIST_S2	Benign	0.46	T
MetaRNN	Benign	0.0018	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	-1.0	N
MutationTaster	Benign	1.0	P
PrimateAI	Benign	0.33	T
PROVEAN	Benign	0.26	N
REVEL	Benign	0.059
Sift	Benign	0.20	T
Sift4G	Uncertain	0.027	D
Polyphen		0.14	B
Vest4		0.034
MPC		0.088
ClinPred		0.0061	T
GERP RS		4.6
Varity_R		0.026
gMVP		0.38

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: rs3740168; hg19: chr10-16948390; COSMIC: COSV64710799;