10-16955267-G-T

Variant names:

• chr10-16955267-G-T
• rs10904849
• NM_001081.4:c.4696-719C>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001081.4(CUBN):​c.4696-719C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.251 in 150,788 control chromosomes in the GnomAD database, including 5,417 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.25 (5417 hom., cov: 27)
• Consequence: CUBN NM_001081.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.576
• Publications: 11 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.97).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.322 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.4696-719C>A		intron	N/A	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.4696-719C>A		intron	N/A	ENSP00000367064.4	O60494

Frequencies

GnomAD3 genomes AF: 0.251 AC: 37764 AN: 150674 Hom.: 5406 Cov.: 27

Gnomad AFR AF: 0.116

Gnomad AMI AF: 0.408

Gnomad AMR AF: 0.197

Gnomad ASJ AF: 0.330

Gnomad EAS AF: 0.156

Gnomad SAS AF: 0.263

Gnomad FIN AF: 0.370

Gnomad MID AF: 0.269

Gnomad NFE AF: 0.326

Gnomad OTH AF: 0.243

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.251 AC: 37795 AN: 150788 Hom.: 5417 Cov.: 27 AF XY: 0.250 AC XY: 18360 AN XY: 73564

African (AFR) AF: 0.117 AC: 4801 AN: 41118

American (AMR) AF: 0.196 AC: 2968 AN: 15114

Ashkenazi Jewish (ASJ) AF: 0.330 AC: 1144 AN: 3466

East Asian (EAS) AF: 0.156 AC: 787 AN: 5046

South Asian (SAS) AF: 0.263 AC: 1252 AN: 4756

European-Finnish (FIN) AF: 0.370 AC: 3821 AN: 10320

Middle Eastern (MID) AF: 0.266 AC: 77 AN: 290

European-Non Finnish (NFE) AF: 0.326 AC: 22048 AN: 67670

Other (OTH) AF: 0.250 AC: 525 AN: 2096

Alfa AF: 0.280 Hom.: 856

Bravo AF: 0.232

Asia WGS AF: 0.221 AC: 769 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
CADD	Benign	0.91
DANN	Benign	0.37
PhyloP100		-0.58
Mutation Taster		=100/0	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: rs10904849; hg19: chr10-16997266;