NM_001081.4:c.8950A>G

Variant names:

• chr10-16877053-T-C
• rs1801239
• NM_001081.4:c.8950A>G

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.8950A>G​(p.Ile2984Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0973 in 1,613,908 control chromosomes in the GnomAD database, including 8,352 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.078 (551 hom., cov: 32)
  • Exomes 𝑓: 0.099 (7801 hom.)
• Consequence: CUBN NM_001081.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 1.65
• Publications: 71 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=0.0022598207).
• BP6: Variant 10-16877053-T-C is Benign according to our data. Variant chr10-16877053-T-C is described in ClinVar as Benign. ClinVar VariationId is 299389.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.117 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.8950A>G	p.Ile2984Val	missense	Exon 57 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.8950A>G	p.Ile2984Val	missense	Exon 57 of 67	ENSP00000367064.4	O60494

Frequencies

GnomAD3 genomes AF: 0.0785 AC: 11937 AN: 152038 Hom.: 550 Cov.: 32

Gnomad AFR AF: 0.0303

Gnomad AMI AF: 0.123

Gnomad AMR AF: 0.0801

Gnomad ASJ AF: 0.150

Gnomad EAS AF: 0.00174

Gnomad SAS AF: 0.126

Gnomad FIN AF: 0.0783

Gnomad MID AF: 0.114

Gnomad NFE AF: 0.105

Gnomad OTH AF: 0.0934

GnomAD2 exomes AF: 0.0893 AC: 22381 AN: 250742 AF XY: 0.0931

Gnomad AFR exome AF: 0.0295

Gnomad AMR exome AF: 0.0723

Gnomad ASJ exome AF: 0.141

Gnomad EAS exome AF: 0.00109

Gnomad FIN exome AF: 0.0757

Gnomad NFE exome AF: 0.103

Gnomad OTH exome AF: 0.0987

GnomAD4 exome AF: 0.0993 AC: 145165 AN: 1461752 Hom.: 7801 Cov.: 33 AF XY: 0.101 AC XY: 73143 AN XY: 727184

African (AFR) AF: 0.0282 AC: 943 AN: 33480

American (AMR) AF: 0.0729 AC: 3260 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.138 AC: 3594 AN: 26136

East Asian (EAS) AF: 0.000932 AC: 37 AN: 39688

South Asian (SAS) AF: 0.133 AC: 11452 AN: 86258

European-Finnish (FIN) AF: 0.0793 AC: 4235 AN: 53408

Middle Eastern (MID) AF: 0.129 AC: 742 AN: 5768

European-Non Finnish (NFE) AF: 0.103 AC: 115045 AN: 1111910

Other (OTH) AF: 0.0970 AC: 5857 AN: 60392

GnomAD4 genome AF: 0.0784 AC: 11933 AN: 152156 Hom.: 551 Cov.: 32 AF XY: 0.0766 AC XY: 5698 AN XY: 74370

African (AFR) AF: 0.0303 AC: 1259 AN: 41536

American (AMR) AF: 0.0800 AC: 1222 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.150 AC: 521 AN: 3470

East Asian (EAS) AF: 0.00174 AC: 9 AN: 5172

South Asian (SAS) AF: 0.125 AC: 604 AN: 4816

European-Finnish (FIN) AF: 0.0783 AC: 828 AN: 10580

Middle Eastern (MID) AF: 0.112 AC: 33 AN: 294

European-Non Finnish (NFE) AF: 0.105 AC: 7152 AN: 67982

Other (OTH) AF: 0.0915 AC: 193 AN: 2110

Alfa AF: 0.0957 Hom.: 3479

Bravo AF: 0.0749

TwinsUK AF: 0.110 AC: 407

ALSPAC AF: 0.0999 AC: 385

ESP6500AA AF: 0.0336 AC: 148

ESP6500EA AF: 0.103 AC: 889

ExAC AF: 0.0900 AC: 10930

Asia WGS AF: 0.0600 AC: 210 AN: 3478

EpiCase AF: 0.108

EpiControl AF: 0.107

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	Imerslund-Grasbeck syndrome (1)
-	-	1	Imerslund-Grasbeck syndrome type 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.67	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	11
DANN	Benign	0.81
DEOGEN2	Benign	0.036	T
Eigen	Benign	-0.44
Eigen_PC	Benign	-0.27
FATHMM_MKL	Benign	0.71	D
LIST_S2	Benign	0.55	T
MetaRNN	Benign	0.0023	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.97	L
PhyloP100		1.6
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-0.38	N
REVEL	Benign	0.12
Sift	Benign	0.41	T
Sift4G	Benign	0.099	T
Polyphen		0.016	B
Vest4		0.052
MPC		0.074
ClinPred		0.0020	T
GERP RS		3.6
Varity_R		0.038
gMVP		0.42
Mutation Taster		=97/3	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: rs1801239; hg19: chr10-16919052; COSMIC: COSV64714423;