NM_001081.4:c.6459G>C

Variant names:

• chr10-16925587-C-G
• rs62619939
• NM_001081.4:c.6459G>C

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.6459G>C​(p.Leu2153Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.124 in 1,613,578 control chromosomes in the GnomAD database, including 12,869 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.13 (1241 hom., cov: 32)
  • Exomes 𝑓: 0.12 (11628 hom.)
• Consequence: CUBN NM_001081.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.0550
• Publications: 17 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: Labcorp Genetics (formerly Invitae), Ambry Genetics, Laboratory for Molecular Medicine
• 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=0.002035886).
• BP6: Variant 10-16925587-C-G is Benign according to our data. Variant chr10-16925587-C-G is described in ClinVar as Benign. ClinVar VariationId is 299438.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.164 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.6459G>C	p.Leu2153Phe	missense	Exon 42 of 67	NP_001072.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CUBN	ENST00000377833.10	TSL:1 MANE Select	c.6459G>C	p.Leu2153Phe	missense	Exon 42 of 67	ENSP00000367064.4

Frequencies

GnomAD3 genomes AF: 0.129 AC: 19587 AN: 152016 Hom.: 1242 Cov.: 32

Gnomad AFR AF: 0.138

Gnomad AMI AF: 0.217

Gnomad AMR AF: 0.123

Gnomad ASJ AF: 0.164

Gnomad EAS AF: 0.0621

Gnomad SAS AF: 0.173

Gnomad FIN AF: 0.136

Gnomad MID AF: 0.155

Gnomad NFE AF: 0.122

Gnomad OTH AF: 0.133

GnomAD2 exomes AF: 0.130 AC: 32624 AN: 251116 AF XY: 0.131

Gnomad AFR exome AF: 0.135

Gnomad AMR exome AF: 0.145

Gnomad ASJ exome AF: 0.153

Gnomad EAS exome AF: 0.0534

Gnomad FIN exome AF: 0.132

Gnomad NFE exome AF: 0.121

Gnomad OTH exome AF: 0.136

GnomAD4 exome AF: 0.123 AC: 180333 AN: 1461444 Hom.: 11628 Cov.: 33 AF XY: 0.125 AC XY: 90722 AN XY: 727058

African (AFR) AF: 0.138 AC: 4627 AN: 33458

American (AMR) AF: 0.143 AC: 6371 AN: 44690

Ashkenazi Jewish (ASJ) AF: 0.151 AC: 3943 AN: 26130

East Asian (EAS) AF: 0.0702 AC: 2785 AN: 39696

South Asian (SAS) AF: 0.177 AC: 15295 AN: 86242

European-Finnish (FIN) AF: 0.133 AC: 7079 AN: 53416

Middle Eastern (MID) AF: 0.153 AC: 869 AN: 5668

European-Non Finnish (NFE) AF: 0.119 AC: 131784 AN: 1111774

Other (OTH) AF: 0.126 AC: 7580 AN: 60370

GnomAD4 genome AF: 0.129 AC: 19600 AN: 152134 Hom.: 1241 Cov.: 32 AF XY: 0.129 AC XY: 9600 AN XY: 74378

African (AFR) AF: 0.138 AC: 5742 AN: 41492

American (AMR) AF: 0.123 AC: 1884 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.164 AC: 570 AN: 3470

East Asian (EAS) AF: 0.0625 AC: 323 AN: 5172

South Asian (SAS) AF: 0.173 AC: 836 AN: 4820

European-Finnish (FIN) AF: 0.136 AC: 1436 AN: 10572

Middle Eastern (MID) AF: 0.156 AC: 46 AN: 294

European-Non Finnish (NFE) AF: 0.122 AC: 8290 AN: 68012

Other (OTH) AF: 0.130 AC: 275 AN: 2114

Alfa AF: 0.103 Hom.: 330

Bravo AF: 0.127

TwinsUK AF: 0.120 AC: 444

ALSPAC AF: 0.111 AC: 429

ESP6500AA AF: 0.133 AC: 586

ESP6500EA AF: 0.120 AC: 1036

ExAC AF: 0.130 AC: 15792

Asia WGS AF: 0.128 AC: 446 AN: 3478

EpiCase AF: 0.123

EpiControl AF: 0.122

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.35
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Benign	0.26	T
Eigen	Uncertain	0.26
Eigen_PC	Benign	0.13
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.87	D
MetaRNN	Benign	0.0020	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Pathogenic	3.0	M
PhyloP100		0.055
PrimateAI	Benign	0.41	T
PROVEAN	Uncertain	-3.0	D
REVEL	Benign	0.28
Sift	Uncertain	0.0090	D
Sift4G	Uncertain	0.0060	D
Polyphen		1.0	D
Vest4		0.22
MutPred		0.61		Gain of catalytic residue at L2153 (P = 0.0325)
MPC		0.46
ClinPred		0.031	T
GERP RS		0.62
Varity_R		0.30
gMVP		0.62
Mutation Taster		=89/11	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs62619939; hg19: chr10-16967586; COSMIC: COSV64708526;