10-16828913-G-T

Variant names:

• chr10-16828913-G-T
• rs1801232
• NM_001081.4:c.10656C>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001081.4(CUBN):​c.10656C>A​(p.Asn3552Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0819 in 1,614,018 control chromosomes in the GnomAD database, including 6,257 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 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. N3552N) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.066 (473 hom., cov: 31)
  • Exomes 𝑓: 0.084 (5784 hom.)
• Consequence: CUBN NM_001081.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 2.26
• Publications: 29 publications found

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]

CUBN Gene-Disease associations (from GenCC):

• Imerslund-Grasbeck syndrome type 1

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Laboratory for Molecular Medicine, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• proteinuria, chronic benign

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• Imerslund-Grasbeck syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0049888194).
• BP6: Variant 10-16828913-G-T is Benign according to our data. Variant chr10-16828913-G-T is described in ClinVar as Benign. ClinVar VariationId is 299358.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.137 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001081.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CUBN	NM_001081.4	MANE Select	c.10656C>A	p.Asn3552Lys	missense	Exon 66 of 67	NP_001072.2	O60494

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CUBN	ENST00000377833.10	TSL:1 MANE Select	c.10656C>A	p.Asn3552Lys	missense	Exon 66 of 67	ENSP00000367064.4	O60494

Frequencies

GnomAD3 genomes AF: 0.0661 AC: 10049 AN: 152096 Hom.: 467 Cov.: 31

Gnomad AFR AF: 0.0162

Gnomad AMI AF: 0.134

Gnomad AMR AF: 0.0364

Gnomad ASJ AF: 0.0559

Gnomad EAS AF: 0.146

Gnomad SAS AF: 0.131

Gnomad FIN AF: 0.150

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.0794

Gnomad OTH AF: 0.0583

GnomAD2 exomes AF: 0.0874 AC: 21977 AN: 251466 AF XY: 0.0912

Gnomad AFR exome AF: 0.0155

Gnomad AMR exome AF: 0.0301

Gnomad ASJ exome AF: 0.0621

Gnomad EAS exome AF: 0.154

Gnomad FIN exome AF: 0.145

Gnomad NFE exome AF: 0.0838

Gnomad OTH exome AF: 0.0754

GnomAD4 exome AF: 0.0836 AC: 122206 AN: 1461804 Hom.: 5784 Cov.: 33 AF XY: 0.0853 AC XY: 62041 AN XY: 727210

African (AFR) AF: 0.0130 AC: 434 AN: 33480

American (AMR) AF: 0.0305 AC: 1363 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0628 AC: 1642 AN: 26136

East Asian (EAS) AF: 0.114 AC: 4535 AN: 39698

South Asian (SAS) AF: 0.132 AC: 11364 AN: 86258

European-Finnish (FIN) AF: 0.141 AC: 7551 AN: 53420

Middle Eastern (MID) AF: 0.0621 AC: 358 AN: 5768

European-Non Finnish (NFE) AF: 0.0809 AC: 89907 AN: 1111928

Other (OTH) AF: 0.0837 AC: 5052 AN: 60392

GnomAD4 genome AF: 0.0661 AC: 10059 AN: 152214 Hom.: 473 Cov.: 31 AF XY: 0.0703 AC XY: 5232 AN XY: 74388

African (AFR) AF: 0.0162 AC: 671 AN: 41542

American (AMR) AF: 0.0363 AC: 556 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0559 AC: 194 AN: 3472

East Asian (EAS) AF: 0.146 AC: 752 AN: 5162

South Asian (SAS) AF: 0.131 AC: 631 AN: 4822

European-Finnish (FIN) AF: 0.150 AC: 1582 AN: 10578

Middle Eastern (MID) AF: 0.0272 AC: 8 AN: 294

European-Non Finnish (NFE) AF: 0.0794 AC: 5404 AN: 68024

Other (OTH) AF: 0.0658 AC: 139 AN: 2114

Alfa AF: 0.0724 Hom.: 1235

Bravo AF: 0.0541

TwinsUK AF: 0.0828 AC: 307

ALSPAC AF: 0.0864 AC: 333

ESP6500AA AF: 0.0177 AC: 78

ESP6500EA AF: 0.0751 AC: 646

ExAC AF: 0.0886 AC: 10751

EpiCase AF: 0.0738

EpiControl AF: 0.0756

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Imerslund-Grasbeck syndrome type 1 (2)
-	-	2	not provided (2)
-	-	1	Imerslund-Grasbeck syndrome (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.79	T
BayesDel_noAF	Benign	-0.76
CADD	Benign	16
DANN	Benign	0.64
DEOGEN2	Benign	0.028	T
Eigen	Benign	-0.30
Eigen_PC	Benign	-0.21
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Benign	0.69	T
MetaRNN	Benign	0.0050	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.1	L
PhyloP100		2.3
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.56	N
REVEL	Benign	0.10
Sift	Benign	0.90	T
Sift4G	Uncertain	0.059	T
Polyphen		0.53	P
Vest4		0.11
MutPred		0.67		Gain of ubiquitination at N3552 (P = 0.0311)
MPC		0.18
ClinPred		0.018	T
GERP RS		4.0
Varity_R		0.053
gMVP		0.45
Mutation Taster		=91/9	polymorphism (auto)

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

Other links and lift over

dbSNP: rs1801232; hg19: chr10-16870912; COSMIC: COSV64706963;